Integrated approach to reducing polypharmacy in older people: exploring the role of oxidative stress and antioxidant potential therapy

ABSTRACT

Increased life expectancy, attributed to improved access to healthcare and drug development, has led to an increase in multimorbidity, a key contributor to polypharmacy. Polypharmacy is characterised by its association with a variety of adverse events in the older persons. The mechanisms involved in the development of age-related chronic diseases are largely unknown; however, altered redox homeostasis due to ageing is one of the main theories. In this context, the present review explores the development and interaction between different age-related diseases, mainly linked by oxidative stress. In addition, drug interactions in the treatment of various diseases are described, emphasising that the holistic management of older people and their pathologies should prevail over the individual treatment of each condition.

KEYWORDS:

• Polypharmacy
• multimorbidity
• frailty
• geriatrics
• inflammaging
• ageing
• oxidative stress
• antioxidants

1. Introduction

The world is experiencing a demographic shift in which the population aged 65 and over is increasing rapidly compared to other age groups. This group of people worldwide is expected to grow from 761 million in 2021 to 1.6 billion in 2050, according to United Nations estimates [1]. This demographic transition is the result of declining fertility rates coupled with an increase in life expectancy, as older adults are now living longer due to technological advances. However, living longer does not necessarily involve a better life quality. In fact, as the number of older people increases, so does the prevalence of chronic non-communicable diseases and disability. In this context, multimorbidity, understood as the development of 2 or more chronic pathologies in an individual, is currently considered a public health problem that affects, according to some estimates, more than half of the population over 60 years of age [2]. The main diseases being experienced by older adults are cardiovascular diseases (CVD) first, followed by type 2 diabetes mellitus (DM2), musculoskeletal disorders, respiratory diseases, cancer and mental health disorders [3]. This increase in age-related chronic diseases has led to more prescription of medicines for the management of these diseases, with the main consequence being an increase in the prevalence of polypharmacy.

1.1. Polypharmacy

Polypharmacy corresponds to a geriatric syndrome whose definition is often very heterogeneous; however, according to a systematic review, the most widely used definition is usually the one that considers the consumption of 5 or more drugs. Whereas hyperpolypharmacy or also called excessive polypharmacy is the concurrent use of 10 or more drugs [4]. This heterogeneity in definition between countries makes it difficult to calculate prevalence; however, some studies worldwide estimated overall 37% of the population over 65 years of age consume 5 or more drugs [5] This geriatric syndrome is associated with an increase in various adverse health outcomes in older people, such as falls, cognitive impairment, disability, hospitalizations, adverse drug reactions, increased hospital stay, among others. These adverse outcomes are increased in frail older people, where frailty is understood as a clinically recognizable condition of increased vulnerability as a result of age-related decline in the reserve and function of various physiological systems, leading to reduced resistance to endogenous and exogenous stressors [6,7].

Thus, polypharmacy was born as a form of management implemented by health systems to address the multimorbidity of the elderly, where factors such as limited consultation time, inadequate coordination of services, lack of evidence, limited availability of geriatricians, among other factors, end up promoting the treatment of different conditions in an individualized manner without taking into consideration the integrity of the geriatric patient, where interactions between diseases and medications are common [8]. This favors phenomena such as cascade prescribing, which is one of the main forms of inappropriate prescribing [9]. In this context, the development of geroscience has enabled research into possible interventions that address the physiology of ageing in an attempt to prevent and reduce the severity of age-related chronic diseases [10]. It is in this sense that this manuscript aims to address therapies aimed at modulating oxidative stress, given that by targeting one of the main substrates of ageing, in the long term they would be expected to eliminate multimorbidity, the indication of therapeutic drugs and thus polypharmacy.

2. Geriatric pharmacology

Ageing has been defined as a normal physiological process characterized by the degeneration over time of cellular and molecular structures that lead to a deterioration of function and organic reserve, limiting the capacity to respond to stressors. All these changes eventually lead to the development of diseases and the death of organisms [4]. The changes attributed to ageing include alterations in response to medication due to pharmacokinetic and pharmacodynamic changes. Pharmacokinetics can be understood in simple terms as how the organism affects the drug, while pharmacodynamics corresponds to how the drug affects the organism [11]. The main changes in geriatric pharmacology are largely due to reduced target organ function, changes in receptor sensitivity, altered homeostasis, concurrent drug use, complexity of concomitant disease states, among others. This section briefly describes the main pharmacokinetic changes produced by age.

2.1. Absorption

Ageing generates substantial changes in the gastrointestinal tract that have a negative impact on the uptake and absorption of orally administered medicines. The main changes observed are at the level of the stomach and distal gastrointestinal tract. At the level of the stomach, a decrease in acid secretion is described as a result of the increased prevalence of atrophic gastritis, which is enhanced by the chronic use of proton pump inhibitors in the older adult population [12,13]. All this generates an increase in pH, altering the solubilization of drugs that behave as weak acids or bases. Thus, an increase in pH would be expected to decrease in vivo dissolution and absorption of weakly basic drugs, but increase in vivo dissolution and absorption of weakly acidic drugs [14,15]. Gastrointestinal motility is also affected by the decrease in cholinergic neurons in the myenteric plexus due to age and concomitant diseases, which is reflected in a decrease in peristalsis and gastric emptying, leading to delayed absorption of certain drugs and increased exposure to the gastrointestinal tract depending on where they are absorbed [16–18].

Not only gastrointestinal absorption is affected by age but also other routes of absorption such as transdermal and inhalation. For example, it has been observed that older adults are more sensitive to transdermal fentanyl patches than younger subjects [19], which could be due to a decrease in the thickness of the epidermis and a weakening of the dermis [20]. In addition, the inhalation pathway also suffers from alterations due to age-related changes in respiratory physiology. This is why elderly patients, as a result of the degradation of elastic fibers, experience a decrease in the total alveolar surface area due to an increase in air spaces, which can be enhanced by smoking, in addition to a loss in the elasticity of the rib cage due to ossification of the rib cartilages, weakening of the respiratory muscles and loss of height of the intervertebral discs [21,22]. These changes lead to an impairment in the respiratory mechanics of the older adult that may influence the absorption of inhaled drugs [23].

2.2. Distribution

Another pharmacokinetic parameter that is altered during ageing is the distribution of drugs in the body. Body water decreases by 10-15% in older adults compared to younger people. This decrease is presumed to be due to a loss of intracellular water, as the extracellular volume remains relatively constant. Parallel to the decrease in body water, there is a decrease in muscle mass and an increase in body fat, particularly visceral fat tissue [24–28]. These changes lead to alterations in the volume of distribution of water- and fat-soluble drugs. In this way, a decrease in the volume of distribution of water-soluble drugs (e.g. digoxin, ethanol, aminoglycosides, theophylline, etc.) is generated, reaching increased plasma concentrations of the latter in a shorter time compared to younger subjects [29,30]. In turn, fat-soluble drugs (e.g. benzodiazepines) will suffer an increased volume of distribution and an increased half-life due to accumulation in adipose tissue [31].

In addition to changes in body composition, there are changes linked to plasma protein binding. In this sense, the decrease in serum albumin concentration and the modification of drug binding sites due to ageing are described. However, age alone is not a determinant of serum albumin alterations, but rather due to age-related pathologies such as malnutrition, sarcopenia and inflammatory diseases [32–34]. These changes in albumin can lead to increased free plasma concentrations of acidic drugs that have a high affinity for albumin, such as diazepam, warfarin, salicylic acid, phenytoin, among others. In parallel to changes in albumin, changes in the concentrations of acid glycoprotein 1 alpha have been described as a result of the inflammatory state of the pathologies that accompany ageing [35,36]. These changes in protein concentrations will not have a major effect on most drugs, since changes in the free fraction will be compensated in parallel by changes in drug excretion, but they will be relevant to the pharmacodynamic action of drugs toward a narrow therapeutic index [37].

2.3. Metabolism and excretion

Most tissues have some capacity to metabolize drugs, however, the main organ responsible for drug metabolism is the liver. It is precisely this process that is affected by ageing due to different factors, such as the decrease in hepatic blood flow, describing a decrease of approximately 20-50% of blood flow in older adults [38], which could alter the transport of drugs to the liver and the supply of oxygen to hepatocytes, which is necessary for phase I oxidation reactions. This is compounded by a decrease in liver volume and blood flow, affecting the cytochrome P450 activity and changing the drug metabolism, increasing susceptibility to drug-induced liver injury [39]. Lipophilic drugs may exhibit an expanded distribution volume, resulting in an extended half-life, while drugs that readily dissolve in water often show a more limited distribution volume. Among the elderly population, certain medications can experience a reduction of up to 30% in hepatic drug clearance, with a higher likelihood of impaired CYP-mediated phase I reactions compared to phase II metabolism. Related to this, CYP3A activity, the most important cytochrome P450 isoforms responsible for drug metabolism by humans, is reduced in ageing [40,41]. Another phenomenon that alters hepatic metabolism in older adults is polypharmacy due to the action of different drugs on liver enzyme levels and activity, making it difficult to study their pharmacokinetics and the role of enzymes in decreasing hepatic clearance.

Renal function is also altered in older adults; in fact, the kidneys are among the organs that undergo the most marked changes during the normal ageing process [42]. These changes are characterized by a progressive reduction in parenchymal thickness and total renal volume. Some studies have described a decrease in volume of around 16 and 22 cm3 per decade from the age of 50 [43–45]. These microstructural alterations are mainly associated with the reduction of functioning nephrons due to nephrosclerosis [46,47], which is reflected in the glomerular filtration rate (GFR). Thus, some studies postulate that the average annual decline in GFR ranges from 0.4 to 2.6 ml/min/1.73 m2 and that after the age of 35 years GFR falls by approximately 5-10% per decade [48–50]. It should be mentioned that the progression of these changes will be enhanced in the presence of hypertension. These morphological and functional renal impairments are accompanied by a decrease in renal blood flow and alterations in the renal flow autoregulatory mechanism, characterized by increased vasoconstrictor responses and decreased vasodilator responses [51]. These age-related changes in renal function have a number of clinical implications, including increased half-life of renally excreted drugs, and increased susceptibility to acute kidney injury (AKI) due to the nephrotoxicity of some drugs [52].

3. Changes in redox homeostasis in the older life stages

The mechanisms involved in ageing are not fully understood. However, attempts have been made to characterize the classical ageing phenotype, given nine features that accompany the normal ageing process. These include: genomic instability, telomere attrition, epigenetic alterations, prosthesis loss, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell depletion, altered intercellular communication, disabled macroautophagy, chronic inflammation and dysbiosis [53]. In this context, different theories have emerged as an attempt to link these characteristics so that they do not remain isolated events that occur during ageing. One of these theories is the one that proposes that the accumulation of oxidative stress is associated with the development of chronic inflammation, which would generate a deterioration of all the cells of an individual, having a greater impact on the homeostatic systems, i.e. nervous, endocrine and immune systems, which would explain the increased morbidity and mortality of population during ageing [54].

Oxidative and nitrosative stress represent mechanisms of damage in various pathologies. One of the latest definitions given by the scientific community characterizes it as an alteration of redox signaling and control, leading to disturbances in redox homeostasis and damage to biomolecules [55]. The main free radicals generated are reactive oxygen species (ROS), which, in the presence of nitric oxide (NO), can be converted into reactive oxygen and nitrogen species, being much more reactive than when on their own. These molecules, at certain concentrations, support fundamental life processes, serving as a defense mechanism against infectious agents and in the function of various cell signaling systems. However, when they increase above the physiological range and overwhelm adaptive systems, this leads to altered redox signaling and cellular damage [56,57].

The generation of free radicals in the cell occurs both by enzymatic action and in free form. The main sources of free radicals are oxidative phosphorylation in the inner membrane of mitochondria and NADPH oxidase (NOX) in activated leukocytes during the respiratory burst process [58]. In addition, reactions catalyzed by the enzymes myeloperoxidase and nitric oxide synthase (NOS) are added when it is uncoupled due to the loss of the cofactor tetrahydrobiopterin (BH4) and acquires the ability to synthesize superoxide anion instead of nitric oxide [59]. However, the enzymatic pathway is not the only route by which free radicals are generated; they can also be generated spontaneously, as in the Fenton and Haber–Weiss reactions in the presence of free ionic iron [60].

Antioxidant defenses can be divided into enzymatic and non-enzymatic antioxidants. Antioxidant enzymes include superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), among others (Figure 1) [61]. The antioxidant response is mainly regulated by the Nrf2/Keap1 system. Nuclear factor erythroid 2 (Nrf2) is a transcription factor that, upon dimerization, binds to promoter regions called antioxidant response elements (ARE), regulating the expression of many cytoprotective enzyme genes, most notably antioxidant enzymes. Under normal conditions, the adaptor protein Keap1 negatively regulates Nrf2; however, upon exposure to oxidative stress, Keap1 loses its ability to ubiquitinate Nrf2, allowing the activation of its target genes (Figure 1) [62].

Figure 1. Molecular mechanism of oxidative stress and potential targets for antioxidant treatment in aging-related diseases. ARE, antioxidant response elements; CAT, catalase, GLP-1, glucagon-like peptide 1;GPX, glutathione peroxidase; GST, glutathione transferase; HO-1, heme oxygenase 1; Keap1, Kelch-like ECH-associated protein 1; NF-κB, nuclear factor kappa-light-chain-enhancer of the activated B cells; Nrf2, nuclear factor-erythroid 2-related factor 2; NSAIDs, non-steroidal anti-inflammatory drugs; ROS, reactive oxygen species; SOD, superoxide dismutase.

Non-enzymatic antioxidants include those produced naturally by cells, such as glutathione, uric acid, bilirubin, and iron-sequestering ferritin, and those that are not produced naturally and must therefore be administered through diet or supplements, such as certain vitamins (A, C, and E), and polyphenols such as curcumin and resveratrol, among many others [63].

It is precisely the homeostasis of this system that is altered during ageing, since on the one hand there is an increase in ROS production, and a parallel decrease in the activity of enzymatic antioxidant systems, leaving cells susceptible to oxidative damage. The increase in free radicals is largely due to mitochondrial dysfunction, in which the efficiency of the electron transport chain is reduced, leading to increased electron leakage parallel to reduced ATP production. This has been studied in different models and tissues, showing that for example in cardiomyocytes complexes III and IV are those that lose their activity with age [64–66], whereas in brain, skeletal muscle and liver complex I is the most sensitive to ageing [67]. On the other hand, the deterioration of antioxidant systems has also been studied, as exemplified by a study in which the activity of the enzyme GPX was measured in a cohort of disabled older women, observing that after the age of 65 years, GPX activity decreased with age [68]. In addition, studies in different models have shown that the expression of SOD decreases with age in cartilage, thereby increasing the risk of developing degenerative diseases such as osteoarthritis [69–71].

Mitochondrial dysfunction represents a common mechanism of damage in various diseases related to ageing, in this sense, in addition to the aforementioned defect in the efficiency of the electron chain, multiple changes have been described in the mitochondria that alter its function, such as; mitochondrial DNA (mtDNA) mutations [72], alterations in mitochondrial proteolysis [73,74], alterations in the dynamic processes of mitochondrial fusion, fission and mitophagy [75–77], among others. It is noteworthy that mtDNA, unlike the cell's nuclear DNA, is more exposed to damage from ROS generated in the mitochondrial inner membrane and has limited repair mechanisms to counteract mutations without histone protection, and it is precisely the accumulation of mtDNA mutations that is one of the central mechanisms that explain mitochondrial dysfunction during aging [78,79]. In this context, during the last decade, various therapies have been described based on lifestyle changes that promote the consumption of natural antioxidants and physical activity, since both processes are presumed to be related to regulating mitochondrial function, which would help treat diseases and prolong longevity [80–84].

In this way, ageing is naturally related to an increase in oxidative stress, which leads to damage and the development of various diseases, although there are various factors that can contribute to modulating this process. In this way, we can describe those factors that accelerate this process, such as the consumption of drugs, alcohol, smoking, sedentary lifestyle, overeating, radiation, atmospheric pollutants, among others [85–88]. It is also possible to describe those factors that reduce oxidative stress, such as the consumption of foods rich in antioxidants or physical activity. Thus, oxidative stress becomes a pharmacological target for the treatment and prevention of various diseases associated with ageing.

4. Effect of aging diseases and their treatment on the redox balance

As mentioned above, the increase in life expectancy due to improved access to healthcare and drug development has been accompanied by an increase in the prevalence of multimorbidity, which is the main driver of polypharmacy.

On the other hand, longevity assurance processes are intricately governed by a group of genes known as vitagenes which play a pivotal role in maintaining cellular homeostasis, particularly in stress conditions, while also exerting control over the aging process. These genes encode various proteins, including heat shock proteins (Hsp). This is a crucial factor in understanding and potentially mitigating the impact of these health challenges due the role of Hsp and their response in establishing a cytoprotective state across a wide spectrum of human diseases such as inflammatory disorders, cancer, aging-related ailments, and neurodegenerative disorders [89,90].

Recent scientific investigations have shed light on the protective properties of dietary antioxidants that have been demonstrated to confer protection through the activation of hormetic pathways, which notably include vitagenes. Within these pathways are Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Nrf-2/ARE pathway and other kinases and transcription factors [90–92]. The hormetic response and polypharmacy are interconnected through their impact on medication management and healthcare decisions leading to personalized medication approach.

The following section aims to address the development and interaction between different age-related diseases, the main link of which is oxidative stress. In addition, some drug interactions between the different diseases will be described, with the aim of making it clear that the comprehensive treatment of the elderly and their pathologies should be superimposed on the individualized management of each condition.

4.1. Hypertension

According to the WHO, the current definition of hypertension is systolic blood pressure (SBP) equal to or greater than 140 mmHg and/or diastolic greater than 90 mmHg with at least two measurements in consultation and on at least two separate occasions to diagnose it [93] is more prevalent in older people and affects 1.28 billion people worldwide. In recent years, there has been an increase in its prevalence, with 76% of adults aged 65–74 years and 82% of adults aged 75 years and older suffering from hypertension [94–96]. Hypertension is one of the major risk factors predisposing to fatal complications of CVD [97], being a key contributor to the development of stroke, myocardial infarction, heart failure and renal failure [93].

The pathophysiology of essential hypertension is directly related to the development of other age-related diseases, where chronic inflammation and increased oxidative stress are mainly responsible for endothelial dysfunction, which together with impaired compensatory blood pressure mechanisms, such as renal dysfunction leading to increased sodium absorption, abnormal renin-angiotensin-aldosterone system (RAAS) response and overactivation of the sympathetic nervous system, lead to increased total peripheral resistance and afterload, contributing to the development of hypertension [93].

Treatment is the most frequent reason for medical visits and use of chronic prescription drugs and adherence to treatment is poor, with 46% of adults with hypertension unaware that they have the disease. Hypertension can be managed by monotherapy and combination therapies, the latter being the most common, aggravating polypharmacy. There are angiotensin-converting enzyme (ACE) inhibitors, such as enalapril and lisinopril; angiotensin-2 receptor blockers (ARBs), such as losartan and telmisartan. Both ACE inhibitors and ARBs have a protective effect on the kidney, as well as relaxing blood vessels. Dihydropyridine calcium antagonists, such as amlodipine and felodipine, also relax blood vessels. Other drugs used include beta-blockers, such as metoprolol and carvedilol, and thiazide diuretics, such as hydrochlorothiazide and chlorthalidone, which remove excess sodium and water from the body, reducing blood pressure. Among these drugs, the most important are those that pharmacologically target the RAAS, since it has been shown that the decrease in angiotensin II and aldosterone activity results in a decrease in oxidative stress and the release of inflammatory mediators at the cellular level, thereby improving endothelial dysfunction [98]. Thus, research with losartan has shown a reduction in oxidative stress after 12 months, with a decrease in serum and urinary levels of 8-hydroxy-deoxyguanosine (8-OHdG) and nitrotyrosine, as well as an increase in SOD activity. However, this effect is not observed with all antihypertensives, because in this same study Amlodipine did not obtain significant decreases after 12 months in the aforementioned markers [99].

Therapeutic goals in older persons require multiple considerations in relation to their comorbidities, clinical, psychosocial and functional contexts, overall prognosis and goals of care, as all older persons are different, for example, in older patients with high functional reserve aggressive hypertensive treatment would be of great benefit, whereas in frail older patients it would increase adverse events such as orthostasis, falls, syncope and cognitive impairment [100]. Another consideration is the interaction of pharmacotherapy for hypertension with pharmacotherapy for other age-related diseases, for example, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) leading to hypertension leads to an increase in the dose of antihypertensive drugs, leading to an increased risk of AKI [101]. Another common example is the prescription of diuretics to counteract edema secondary to the use of dihydropyridine calcium channel blockers, which significantly decreases the quality of life of older people [102].

It is in this context that redox balance modulation takes on great importance, since the most relevant drugs in the treatment of hypertension are those aimed at reducing endothelial dysfunction by reducing oxidative stress and inflammation, which not only has implications for the management of blood pressure, but also for the treatment of other age-related diseases such as Alzheimer's disease and DM2, as will be discussed below.

4.2. Alzheimer's disease

Among the dementias, Alzheimer's disease (AD) is the most common. AD is a neurodegenerative disease characterized by marked latent cognitive impairment, loss of memory and spatio-temporal orientation. Patients with advanced AD cannot recognize their relatives or where they are. This disease can have a prolonged silent course, however, it can present cognitive impairment to varying degrees which is important to suspect in order to provide a comprehensive approach to the patient and their family early on. Currently, AD is becoming increasingly lethal and is a major cost to the healthcare system, for example, in the United States in 2020 and 2021 it was ranked as the seventh leading cause of death nationwide and the economic costs associated with medical care, long-term care and palliative care for people aged 65 years and older with dementia amounted to $321 billion [103,104]

The brain has characteristics that make it particularly vulnerable to oxidative stress, including its high oxygen consumption (approximately 20% of the oxygen supplied by the respiratory system), its high energy and metabolic demand, as well as its composition of neurons, which are cells with a low antioxidant defense, low regenerative capacity and whose membranes are rich in long-chain polyunsaturated fatty acids (PUFAs) that are preferential targets of ROS in the lipid peroxidation reactions that occur in living cells [105]. As for the pathophysiology of AD, the key point is the deposition of amyloid-β (Aβ) (whose oligomeric forms are the most neurotoxic by causing oxidative stress), which is considered the main inducer of the disease, a phenomenon to which is added Tau hyperphosphorylation, tangle formation and mitochondrial dysfunction, which ultimately lead to neurodegeneration and cognitive impairment.

Oxidative stress would be one of the main promoting factors in Alzheimer's disease as it is the direct result of the damage generated by the accumulation of Aβ, as well as participating directly in the pathogenesis of the disease by promoting the production and aggregation of Aβ, as well as facilitating the phosphorylation of Tau, which leads to a vicious circle marked by neurotoxicity and neuroinflammation, which ultimately leads to neuronal death (Zhao, Yan, 2013). For example, one of the main mechanisms of oxidative stress damage is lipid peroxidation of PUFAs, which has been associated with plasma membrane damage, as well as an increase in toxic second mediators such as 4-hydroxy-2-nonenal aldehyde HNE, malondialdehyde (MDA) and ceramides. In this regard, natural fat-soluble antioxidants such as vitamin E have been shown in in vitro studies to decrease lipid peroxidation and with it toxic mediators [106–109]. As for damage to nucleic acids and proteins, this has been verified by studying biomarkers of oxidative stress in AD, with the accumulation of products such as 8-OHdG, 8-hydroxyguanosine, protein carbonyls and 3-nitrotyrosine residues [110–112]. This whole process of macromolecule damage is aggravated by alterations in the concentrations of transition metals such as iron, zinc and copper, and by alterations in the function of NO, which physiologically at the brain level has functions linked to synaptic plasticity, sleep regulation, appetite and neurosecretion [113–118].

As for the relationship of AD with other age-related comorbidities, a strong association has now been proven, given that those with various comorbidities are at greater risk of suffering and exacerbating cognitive decline [119]. In this regard, the most common comorbidities in people with dementia include DM2, CVD and hypertension. For example, hypertension as a risk factor for the development of AD is directly linked to the role of angiotensin II, which through its G protein-coupled receptor AT1 pathway, induces a variety of deleterious effects at the brain level, including the induction of proinflammatory pathways, ROS synthesis and apoptosis [120,121]. Against this background, treatment with different RAAS modulators has been shown in in vitro and in vivo models to have a beneficial role in the prevention and treatment of cognitive impairment, with ARBs and ACE inhibitors having the strongest evidence. ARBs have shown some superiority in the prevention of cognitive decline compared to ACE inhibitors, for example some clinical trials with telmisartan alone or in combination with other drugs such as rosuvastatin, have been shown to reduce the risk of incidences of dementia or cognitive decline in certain hypertensive patients, however these are still preliminary results that need to be studied with further evidence [122,123].

Currently, there is no curative treatment for AD, as the main focus is on treating symptoms according to the stage of the disease with the aim of providing well-being, dignity and independence for individuals and their families over a longer period of time. For mild to moderate dementia, the pharmacological treatment of choice is cholinesterase inhibitors, such as donepezil, rivastigmine and galantamine, which increase cholinergic transmission by inhibiting cholinesterase in the synaptic gap [124]. A study done in another line of research in relation to metabolic syndrome has shown that galantamine can increase antioxidant enzyme activity, such as SOD and CAT activity, as well as decrease lipid peroxidation and systemic nitrite levels [125]. In this line, a recent study showed an identification of polyphenols as potential inhibitors of cholinesterase and oxidative stress for their antioxidant properties useful in the treatment of AD [126]. Another drug used is Memantine, which has been considered as a neuroprotectant by antagonizing the overstimulation of the N-methyl-D-aspartate (NMDA) receptor [127]. Thus, combined treatment with memantine and cholinesterase inhibitors can be considered, being more useful for AD, but less acceptable to patients [128,129]. However, caution should be exercised with cholinesterase inhibitors in older adults, as they potentiate vagal tone and are contraindicated in cases of initial bradycardia or cardiac conduction pathologies due to the risk of syncope, falls and fractures. In contrast, memantine has no significant side effects [130]. Another precaution to consider in the treatment of people with cognitive impairment is the inappropriate prescription of drugs with anticholinergic effects, which are often prescribed for the treatment of other age-related conditions.

Thus, finally, current evidence supports that the most cost-effective management seems to be the prevention of AD [131], which is achieved with adequate control of the main risk factors, including comorbidities, which as we have seen, are directly related to each other and must be managed in a comprehensive manner.

4.3. Osteoarthritis

Osteoarthritis (OA) is the most common form of arthritis. Over time it degrades cartilage, causes bone remodeling and produces formation of osteophytes visible on radiological examinations. This produces alterations and clinical manifestations such as pain, stiffness, swelling and limitations in joint function, producing high mobility, especially in older adults. Joint's alterations commonly occur in the knee, hip, hand, foot and ankle [132]. OA affects 1 in 3 people over age 65 and is more frequent in women than men. The main risk factors are obesity, physical inactivity, and joint injury [133,134]. Effects of aging on cartilage play an important role in the pathophysiology of OA as well as cellular senescence, inflammation, mitochondrial dysfunction, oxidative stress and energy metabolism dysfunction [135]. OA is associated with chronic low-grade systemic and local inflammation including active synovitis, term known as ‘inflammaging’ provoked by a continuous antigenic load and stress [136]. An important mechanism and a hallmark of aging in OA is the senescence-associated secretory phenotype which increases production of proinflammatory mediators and matrix-degrading enzymes, maintaining the cell in a cycle arrest [137]. Other support for the inflammation is the visceral fat mass that is associated with a decline in muscle mass greater in older adults and with a higher adipocyte and proinflammatory macrophages, increasing cytokines and adipokines [138,139]. Moreover, there exists the term ‘meta-inflammation’ which is related to metabolic syndrome associated with OA and obviously individual factors that are crucial at this point and intermingles with OA such as diabetes, dyslipidemia, and hypertension [140]. These factors can all damage the joint tissue and promote matrix destruction with an alteration of gene expression in chondrocytes [141]. In aged mice, the intrinsic circadian clock is disrupted and in humans OA chondrocytes the alteration in the circadian clock is associated with stress-induced senescence in fibroblasts [142]. Another hallmark of ageing in OA is the mitochondrial dysfunction, leading to the development of the ageing phenotype and oxidative stress [143]. OA chondrocytes have mitochondrial biogenesis impairment, thereby producing chondrocyte pro catabolic responses. Hydrogen peroxide (H₂O₂) downregulates the expression of mitochondrial antioxidant enzymes and may escape from the mitochondria causing oxidative damage to cellular macromolecules [144–146].

Mice with OA showed elevated intracellular and mitochondrial superoxide anion radical (O₂·^_) generation and a decrease in mitochondrial SOD2 together with increased degeneration cartilage age-related. However, the use of antioxidants such as a derivative of vitamin C suppresses mitochondrial superoxide generation and ameliorates cartilage degeneration in vivo [147].

In synovial fluid xanthine oxidoreductase level is elevated in OA and its amount correlates with the severity of joint damage [148]. A reduction in extracellular matrix gene expression and protein synthesis is observed in the anormal function of human chondrocyte insulin-like growth factor 1 signaling due to oxidative stress [149].

The thiol groups that are in proteins which contain reactive cysteines suffer oxidative post-translational modifications in OA chondrocytes, a process called S-sulfenylation that promoted the production of matrix metalloproteinase 13 and increases the cartilage destruction [150]. Hyperoxidation leads to age-related inhibition of pro-survival cell signaling and chondrocyte cell death and the expression of CAT prevents this phenomenon [151]. On the other hand, ferroptosis, a type of nonapoptotic iron-dependent cell death associated with lipid peroxidation and modulated by GPX4 is involved, at least in part, in OA pathogenesis. A recent study showed that iron level in synovial fluid increased with the progression of OA as well as Fe²⁺, Fe³⁺ and total iron concentrations, thus suggesting an iron accumulation during OA progression. GPX4 function is decreased in OA along with decrease of glutathione (GSH) contents in the cartilage. Downregulation of GPX4 increased the sensitivity of chondrocytes to oxidative stress and mitochondrial morphological alteration together with degradation of extracellular matrix through MAPK/NF-κB pathway [152].

There are non-pharmacological treatments based on exercise, weight loss, braces and foot orthoses and education [153]. On the other hand, the classic pharmacological is NSAIDs that should only be used during periods when symptoms are present. Depending on the patient's clinical setting topical capsaicin, duloxetine, and intraarticular glucocorticoids may be required [154], but may have deleterious effects on the hyaline cartilage and may accelerate OA progression [155]. NSAIDs have several anti-inflammatory, analgesic and antipyretic benefits. Although NSAIDs are the first line of treatment, it produces adverse effects in our organism especially when it is self-medicated which include gastrointestinal, cardiovascular, hepatic, renal, cerebral and pulmonary problems. They are toxic compounds due to the activation of mitochondrial oxidative stress and the key target for some of them is the mitochondrial electron transport chain complex-I, leading to abnormal redox-active chain reactions [156].

Given the polypharmacy of patients who use NSAIDs, these drugs can potentiate gastrointestinal, cardiovascular, and renal complications dose-dependent. Gastrointestinal damage are upper gastrointestinal complications, especially peptic ulcer and also can lead to impairment of intestinal mucosal barrier function producing proinflammatory cytokine cascade and NLRP3 inflammasome activation which both attract the neutrophils causing oxidative burst, chronic inflammation, apoptosis and eventually intestinal ulceration [157,158]. Main cardiovascular complications are major vascular events, heart failure and stroke [159]. Regarding kidney complications, users of NSAIDs have 3-fold greater risk for AKI [160] and the treatment should be used with caution in patients with hypertension or heart failure because both treatments significantly increase the risk of AKI and alters the hemodynamic equilibrium [101].

Due to the complexity of OA development it's impossible to analyze all causal factors. However, OA is certainly an ageing-associated process although it has its own independent processes. The treatment with NSAIDs produces a vicious circle of damage and oxidative stress given the chronic use of these drugs.

4.4. Cancer

Another age-related disease is cancer, which has increased in prevalence worldwide, with significant economic and social repercussions. Older adults will account for about 60% of all newly diagnosed cancer cases projected to 2035, with prevention among young adults a key pillar. The main cancers diagnosed worldwide are lung, colorectal, prostate, stomach and breast cancer [161,162]. Regarding the relationship of this pathology with polypharmacy, it has been reported that polypharmacy exceeds 90% in older adults diagnosed with cancer, being even higher in those receiving radiotherapy because the adverse effects of this therapy must be managed with more drugs, thereby increasing their consumption [163]. The link between cancer and oxidative stress can be approached in two contexts, firstly in the pathophysiology that initiates cancer progression and secondly in cancer therapy, where pro-oxidant and antioxidant substances stand out.

Various studies have shown that cancer cells in general have a redox imbalance in favor of the oxidative burden, for example, it has been observed that in lung cancer there is a decrease in vitamin E and a depletion of serum antioxidant capacity, together with an increase in lipid peroxidation, leading to a significant increase in systemic oxidative stress [164]. The increase of ROS in cancer cells, observed to come mainly from mitochondria and the enzyme NOX, thus dysregulation of NOX activity or mitochondria has been found to be linked to transformation and progression of some common cancers, such as bladder, breast, kidney, colon, stomach, chronic lymphocytic leukemia among others [165–171]. This prooxidant state in cancer induces a variety of biological effects including increased cell proliferation and survival [172–174], DNA damage and genomic instability [175,176] and drug and radiotherapy resistance [177,178]. However, this pro-oxidant state is in equilibrium, as toxic levels of ROS induce cell cycle arrest, apoptosis and senescence, whereby cancer cells develop mechanisms by which they partially decrease ROS levels. For example, mutations in the Nrf2/Keap1 system have been described that generate a higher expression of Nrf2 and its target genes, increasing the transcription of antioxidant enzymes [179,180], and tumor cells also adapt to hypoxia by increasing glycolysis metabolism, in a phenomenon known as the Warburg effect, which also plays a role in redox homeostasis by inducing reducing agents such as NADPH via the pentose phosphate pathway or GSH via glutaminolysis [181,182]. In this way, tumor cells manage to maintain a prooxidant redox state that favors tumorigenesis, without reaching high levels of ROS that interfere with their progression.

On the other hand, treatment can also create an environment of oxidative stress. In this sense, radio- and chemotherapeutic drugs have as their main objective to increase ROS production to toxic levels, depleting antioxidant systems and causing apoptosis of tumor cells. An example of this are the anthracyclines, which are cytotoxic drugs commonly used in the treatment of a broad spectrum of cancers. The main theory currently accepted to explain the generation of ROS by anthracyclines indicates that they are forming an unstable metabolite semiquinone, which when oxidized by the mitochondria is accompanied by the release of large quantities of ROS together with apoptosis and ferroptosis [183]. Another theory indicates that anthracyclines form complexes with iron which induces lipid peroxidation, protein carbonylation, DNA oxidation by ROS, leading to tumor cell death by apoptosis and ferroptosis [184]. While these pro-oxidant therapies are often favorable for cancer treatment, they also induce long-term damage in other organs distant from the origin of the cancer, given the non-targeted nature of oxidative damage. Thus, for example, multiple side effects have been described in the use of chemotherapeutics, including cardiotoxicity, neurotoxicity, hepatotoxicity, among others, most of them mediated by oxidative stress [185–193]. In this context, antioxidants have been tested to reduce the side effects of anticancer therapy, including the use of polyphenols, which have been shown to have an antioxidant and anti-inflammatory effect by modulating the NF-κB signaling pathway (Figure 1), which is the main pathway involved in lung, liver and colorectal cancer [194]. Thus, the net effect of the polyphenol is to reduce cytokines and ROS, increase cancer cell apoptosis and enhance vasodilator function through activation of endothelial NOS (eNOS) [195]. In addition, vitamin C also activates eNOS through the same pathway as polyphenols (PI3 kinase/Akt signaling) [196]. Therefore, the use of antioxidants may serve as a complementary therapy for cancer treatment by protecting normal tissues from oxidative stress damage, while enhancing the efficacy of chemo- and radiotherapy.

4.5. Obesity and metabolic disorders

Obesity is a complex multifactorial disease. According to WHO, it is defined as ‘excess or abnormal fat accumulation that presents a risk to health’ [197]. This pathology has an worldwide impact due its increase of prevalence and public health management. Nowadays, despite the fact that body mass index (BMI) has low sensitivity and there is a large inter-individual variability in the percent body fat, it is still used in the clinical setting. According to this index, nearly a third of the world's population is classified as overweight or obese in all ages and both sexes, although the prevalence is generally in older persons and women [198]. The importance of obesity is rooted in its relation with sarcopenia [199], a prevalent condition in elderly, which is overlooked and undertreated in the biomedical setting. This interconnection leads to sarcopenia or even osteosarcopenia exacerbation due to fat infiltration into muscle, hampering of physical functions and underscore adverse outcomes [200].

Intrinsically, obesity is related to many conditions such as metabolic syndrome, DM2, CVD, and hypertension [201]. Oxidative stress is involved in their pathophysiology. While the majority of mechanisms mentioned in other diseases contribute to the pathophysiology of oxidative stress in obesity, there exists a distinct group of antioxidant enzymes known as the paraoxonase family. Notably, paraoxonase 1 is associated with high-density lipoprotein (HDL) and plays a role in hydrolyzing oxidized low-density lipoprotein-cholesterol (LDL). This enzyme possesses atheroprotective properties, but its activity is reduced in conditions such as DM2, metabolic syndrome, hypercholesterolemia, and chronic renal failure [202,203]. Previous studies showed a positive correlation between oxidative stress and insulin resistance with increased LDL as well as low HDL in animal models. HDL sub particles have antioxidant activity and in overweight individuals its antioxidant mechanism is dysfunctional which leads to more metabolic disorders and is associated with accelerated atherosclerosis due to increased macrophage infiltration [204,205]. Moreover, ROS can influence the activity of enzymes involved in lipolysis and lipogenesis [206] and play a role in signal transduction and the regulation of adipocyte differentiation and it is influenced by various factors that are susceptible to redox metabolism, including transcription factors, cell-cycle proteins, hormones, and small molecules. In preadipocytes, NADPH has a role in the generation of ROS [207] On the other hand, mature adipocytes (white, brown, and beige) have different functions throughout life that contribute to maintaining adequate adaptive thermogenesis and homeostasis. In this line, ROS may play a crucial role in the browning of adipose tissue, potentially mitigating obesity, as certain natural compounds with antioxidant properties have been shown to facilitate browning [208]. Chronic excessive nutrient availability leads to disruptions in mitochondrial homeostasis and induces abnormalities in biogenesis, ROS production, and apoptosis [209]. This is aggravated by its association with insulin resistance and DM2 due to elevated glucose levels that contribute to increased ROS production, modifying mitochondrial enzymes and contributing to the development of metabolic disorders. Impaired mitochondrial function in adipocytes is associated with low grade inflammation, disturbances in adipogenesis, lipolysis, fatty acid esterification, adiponectin production and apoptosis [210]. After the mitophagy process undergone by the mitochondria, they are replaced in a process that produces more ROS [211], so it's a vicious circle. Another mechanism occurs when exposed to ROS, redox-sensitive transcription factors like NF-kB become activated, leading to the transcription of various proinflammatory cytokines. This process contributes to an escalation in ROS overproduction, especially H₂O₂ which affects the degradation of IκB, an NF-κB inhibitor [212,213].

Leptin is an adipokine that regulates hunger and appetite and food intake. In overweight individuals there is a elevation of this molecule leading to secretion of pro-inflammatory cytokines, such as TNF-α and IL-6 as well as TGF-β and has a role in cardiac fibrosis and oxidative stress through mTOR pathway [214].

Otherwise, adiponectin is an anti-inflammatory and insulin-sensitizing hormone secreted by adipose tissue and in obese patients is diminished. Adiponectin exhibits anti-inflammatory effects by decreasing the levels of NF-κB [215]. Increased concentrations of adiponectin result in reduced production and activity of TNF-α, IL-6, and other interleukins, promoting lipolysis and stimulating de novo synthesis and secretion of hepatic fatty acids [216].

This same chronic inflammation also increases hepcidin, a hormone which regulates iron metabolism. The elevated levels of hepcidin leads to iron deficiency [217]. Despite this, iron triggers oxidative stress due to its redox activity as a metal. Additionally, it contributes to inflammation, and endocrine dysfunction. Intracellular free iron is cytotoxic as it promotes the Fenton reaction, further intensifying oxidative stress, producing hydroxyl radical [·OH] (Figure 1) [218].

The treatment for obesity and metabolic syndrome is non-pharmacological as an essential pillar. This includes regular physical activity, healthy diet, behavior modification and others actions that include a supportive environment. The diet should be a low-fat low-carbohydrate diet with plenty of antioxidants such as vitamin C and E, and polyphenols [208].

The pharmacological treatment is reserved for those with a BMI >30 kg/m2, or a BMI of 27–29.9 kg/m2 with weight-related comorbidities, who have not met weight loss goals [219]. This is based especially on Glucagon-like peptide-1 (GLP-1) agonists such as Liraglutide or Semaglutide. G⁣⁣LP-1, an incretin hormone, stimulates insulin secretion, suppresses glucagon secretion, and reduces food intake. Besides its hypoglycemic effects, GLP-1 exhibits anti-inflammatory, antioxidative and vascular protective properties in various cells and tissues as well as the suppression of NF-κB [220,221]. In terms of oxidative stress, GLP-1 engages the Nrf2-ARE pathway, which decreases oxidative stress markers and activates genes associated with mitochondrial biogenesis and preservation, including mitochondrial transcription factors [222,223]. Another GLP-1 analog, exendin-4, has demonstrated the ability to reduce H₂O₂-induced ROS production and enhance the synthesis of antioxidant enzymes such as CAT, GPX, and SOD through Nrf2 [224,225]. In this context, it is necessary to consider whether the patient has DM2, their frailty, and whether they are taking other hypoglycemic medications to take into account the risk of falls and hypoglycemia, as well as adverse effects. To end, obesity, metabolic syndrome, and oxidative stress are interconnected conditions that have a significant impact on overall health and well-being and contribute to the development and progression of various chronic diseases that may be managed with antioxidants drugs.

4.6. Ischemic heart disease

Ischemic heart disease is a condition in which there is reduced blood flow to the heart muscle due to the narrowing or blockage of the coronary arteries. The majority of cardiac deaths in adults from countries of any income are due to ischemic heart disease secondary to coronary atherosclerosis [226], a key development factor related to chronic inflammation, oxidative stress, disrupted homeostasis, imbalance in growth, proliferation and migration cell regulation [227]. It is associated with an imbalance of blood supply to the myocardium due to obstruction of the epicardial coronary arteries, often caused by plaque buildup in the wall of the arteries that may cause vascular obstruction and ischemia [228]. During the ischemic phase, there is a decrease in oxygen supply and cellular changes inside that produce an interruption of cellular metabolism and derangements of cellular membrane pumps, causing the anaerobic to predominate over the aerobic metabolism which decreases the cellular pH thus producing that Na⁺/H⁺ exchanger excretes excess hydrogen ions, which produces an influx of Na ⁺. In this phase there is also a endoplasmic reticulum stress, decrease intracellular ATP, reduction of active Ca²⁺ efflux, limiting its reuptake by other organelles such as endoplasmic reticulum or mitochondria, producing an abnormal rise of this ion in the cell which then mediate excitotoxic cell death. These intracellular changes occur in conjunction with the opening of the mitochondrial permeability transition pore (mPTP), which causes depolarization of the mitochondrial membrane potential, further impairing ATP production. Ca²⁺ at high concentrations can contribute to activation of proteases, calpains, and endonucleases, which cause damage to the muscular heart tissue, and DNA, and cell death [229–231].

On the other hand, the reperfusion phase, frequently through percutaneous coronary intervention (PCI), produces a burst of O₂·^_ that causes further damage. Indeed, a reperfusion paradoja occurs since the damage can reach up to 50% of the final size of the infarct, term called myocardial ischemia-reperfusion injury (IRI) [232]. ROS production is an important event in cell signaling transduction maintenance. However, different mechanisms occur in this phase due to disruption of the respiratory chains, commonly associated with complex I, which can lead to an excessive ROS production, aggravating the damage, causing DNA, lipids and protein peroxidation. In fact, it has been known for many years that this phase accelerates the development of necrosis [233] and there is still no effective treatment to prevent myocardial IRI. Other mechanisms are calcium overload, opening of the mPTP, endothelial dysfunction, prothrombogenic phenotype, and inflammatory responses [232]. The main IRI ROS is O₂·^_ which is produced by mitochondria and xanthine oxidase, NOX, cytochrome P450 oxidases and uncoupled NOS. Under physiological conditions is not toxic due the fast dismutation to H₂O₂, a conversion accelerated by SOD. However, under low pH conditions, O₂·^_ converted to its conjugate acid, the more highly potent oxidant, hydroperoxyl radical (HOO•) and although H₂O₂ is less reactive, it diffuses across membranes and can act as a second messenger, participating in the generation of •OH, through the Fenton reaction (Figure 1) in the presence of transition metals [231,234,235]. Besides that, in myocardial IRI there are proinflammatory processes due to the release of cytokines like TNF-α, IL-1β and IL-6 and chemokines which also produces autophagy, necrosis, apoptosis [236].

Globally, the damage is given by both phases. However, the reperfusion phase is a dynamic process that not only occurs at a single time when performing PCI, but contractile and endothelial dysfunction and cell death can continue up to 3 days after the start of reperfusion [237].

Oxidative stress-induced endothelial dysfunction is an early event in the development of this disease, leading to an imbalance between the availability of NO and ROS. This dysfunction is characterized by abnormal regulation of blood vessel tone and growth, impaired anti-inflammatory and anti-thrombotic properties of the endothelium, and disturbances in vascular remodeling [238]. A healthy endothelium plays a crucial role in responding to vascular stress by inducing vasorelaxation, controlling vascular permeability, and preventing platelet aggregation. However, it is highly reactive to various stimuli, including NO, to maintain proper vascular tone and structural integrity. NO, synthesized by eNOS, plays a significant role in the body's antioxidant defense system and reduced bioavailability of NO primarily occurs due to increased degradation by ROS and decreased expression of eNOS. Additionally, uncoupling of eNOS can further decrease NO availability as it shifts its enzymatic activity to generate O₂·− and H₂O₂ instead of NO [239]. On the other hand, angiotensin II and thrombin can upregulate NADPH in response to ROS [240,241].

As previously mentioned, atherosclerosis is the primary underlying cause of ischemic heart disease. It is characterized by a chronic inflammatory condition involving the interaction between immune cells and endothelial cells, facilitated by adhesion molecules present on the surface of the vascular endothelium [242]. Excessive production of ROS contributes to the formation of atherogenic oxidized low-density lipoprotein, a key factor in the development of atherosclerosis [243]. Additionally, ROS overproduction leads to an increase in NADPH levels and impairs mitochondrial capacity, resulting in mitochondrial dysfunction [244]. During the progression of atherosclerosis, accumulated neutrophils generate additional ROS and activate poly [ADP-ribose] polymerase (PARP), causing damage to mtDNA and further ROS production. This oxidative stress and the activation of various cellular pathways lead to the release of inflammatory cytokines, contributing to vascular inflammation and participating in the oxidation process of LDL. These effects are further exacerbated by factors such as age, obesity, smoking, hypertension, DM2, and dyslipidemia [245]. Clinically, the first step in the resolution of heart ischemia in patients who meet the criteria for ST elevation myocardial infarction are thrombolytics or PCI, which is strongly preferred. At this point, patients usually require nitrates, dual antiplatelet therapy, anticoagulation drugs, beta blockers, statins, ACE inhibitors, morphine and oxygen. The long term management includes use of multiple medications prior to being beneficial in the secondary prevention of atherosclerotic disease and congestive heart failure [246].

On the other hand, current research has not provided evidence that antioxidants like flavonoids and vitamins decrease the risk of acute myocardial infarction (AMI) or mitigate myocardial IRI in humans [247,248]. However, other studies have demonstrated that cocoa flavonoids exhibit anti-inflammatory properties, reduce oxidative stress, and inhibit myocardial apoptosis following AMI and reperfusion. These effects are achieved by counteracting membrane peroxidation and nitro-oxidative stress, as well as by reducing levels of inflammatory markers such as IL-6 and NF-κB [249].

It should be noted that the phenomenon of ischemia-reperfusion not only happens in myocardial infarction, but also in stroke, and peripheral vascular disease [231], pathologies that also increase with age and have different management.

4.7. Diabetes mellitus 2

The American Diabetes Association defines DM2 as a progressive loss of adequate β-cell insulin secretion frequently on the background of insulin resistance that manifests clinically as hyperglycemia. Various genetic and environmental factors are involved [250]. The worldwide prevalence is 10.5 percent among adults aged 20–79 years and it is estimated to affect 537 million adults [251].

Chronic hyperglycemia leads to an imbalance between the antioxidant defense system and ROS production with predominance of the latter. Consequently, the development of oxidative stress contributes to diabetic complications by damaging cells, tissues, and organs. It can impair insulin cell signaling, promote endothelial dysfunction, cause DNA damage, and induce inflammation. These effects contribute to the pathogenesis of complications associated with DM2, such as macrovascular damage and microvascular damage (nephropathy, retinopathy, and neuropathy) [252,253].

The main mechanisms are associated with glucose and lipid metabolism [254], which include glucose autoxidation, mitochondrial dysfunction, activation of protein kinase C (PKC) pathway, advanced glycation end products (AGEs) formation and accumulation, and inflammation.

Glucose oxidation pathway is essential for glucose to be oxidized in body cells and is composed of multiple steps that under normal conditions result in increased mitochondrial production of O₂·^_. In hyperglycemic conditions, the antioxidant compensatory mechanism will become overwhelmed, thereby resulting in the production of macromolecules damage, such as DNA oxidation, which responses with activation of PARP-1, a repair enzyme. Consequently, PARP-1 increases the levels of glycolytic intermediates, thus increasing H₂O₂ production, as well as the metabolic flux across pro-oxidative pathways, such as AGE, PKC, hexosamine and polyol ones [255]

Advanced glycation end-products are a complex group of molecules formed through a process called non-enzymatic glycation. This process is accelerated in conditions of hyperglycemia and has an important role in CVD progression in DM2. AGEs can be formed both within the body (endogenously) and in foods during cooking or processing (exogenously). In the context of DM2, endogenous AGEs are of particular interest due to their formation involving a series of chemical reactions that result in the irreversible modification of macromolecules due to cross-linking of proteins, cellular dysfunction, oxidative stress, inflammation and activation of other oxidative stress-related pro-oxidative pathways such as that of PKC when AGEs bind to their receptor [256,257].

The presence of AGEs, particularly in connective tissue, results in age-related damage. It has been demonstrated that the covalent cross-linking of adhesion proteins in the extracellular matrix contributes to the loss of skin and blood vessel elasticity, as well as the degeneration of cartilage, ligaments, and the lens. The accumulation of AGEs, along with the buildup of lipofuscin, is associated with the process of aging and chronic diseases related to age. Another AGEs ageing hallmark is the activation of NF-κB pathway in patients with age-related macular degeneration [258,259]. Uncontrolled DM2 leads to the activation of the polyol pathway, which results in intracellular sorbitol accumulation and its incapability to pass through the cell membrane in insulin-independent tissues, thus contributing to cell damage. The intermediates of this pathway can glycate proteins leading to AGEs formation, aggravating the vascular damage [260]. Moreover, another source of oxidative stress is the formation of the pro-oxidant glyoxal, a precursor of AGEs, which can result from the buildup of glucose in cells [261].

Protein Kinase C is an enzyme playing a crucial role in a wide range of cellular processes and cell signaling pathways. It functions by modifying the activities of other proteins through a cascade of phosphorylation reactions. PKC activation is closely associated with oxidative stress in DM2, creating a vicious cycle. Activation of PKC in DM2 has been linked to several mechanisms that contribute to diabetic complications such as insulin resistance due to impairment of insulin signaling, leading to insulin resistance [262]. In addition, this pathway interferes with the normal translocation of glucose transporter type 4 (GLUT4) to the cell surface, reducing glucose uptake by cells. Moreover, it produces vascular complications, fibrosis and oxidative stress [263]

Heightened activation of the PKC pathway has been shown to stimulate enzymes that generate ROS, such as NADPH-oxidases and lipoxygenases [262]. In addition, PARP activation due to DNA oxidation affects the signal and induces oxidative stress through PKC activation [264]. Inflammation, aging, and oxidative stress are closely intertwined processes that contribute to the pathogenesis of DM2 [265]. The balance between proinflammatory and anti-inflammatory cytokines is essential for the development of muscle insulin resistance and in DM2. Chronic low-grade inflammation is commonly observed, being characterized by increased levels of pro-inflammatory cytokines and activation of immune cells. This inflammatory state is mediated by various factors, including adipose tissue dysfunction, insulin resistance, and metabolic abnormalities [266]. The pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, released during inflammation can further impair insulin signaling and promote insulin resistance. IL-6 has been shown to induce hyperglycemia and compensatory hyperinsulinemia [267,268]. TNF-α, a cytokine with proinflammatory properties, affects lipid metabolism and contributes to insulin resistance by influencing the activity of GLUT4 and inducing phosphorylation of insulin receptor substrate-1 [269,270]. Lipotoxicity, besides causing insulin resistance, also plays a role in pancreatic β cell dysfunction. The activation of ROS and endoplasmic reticulum stress have been identified as the mechanisms that contribute to lipotoxicity in β cells [271].

In the development of this pathology, it is important not to overlook prediabetes, which involves the infiltration of immune cells into adipose tissue and holds a significant role. Macrophages with an M1-like phenotype are known for their proinflammatory characteristics leading to a failure of pancreatic β-cells, while macrophages exhibiting an M2-like phenotype secreting cytokines with anti-inflammatory properties [272]

The treatment of patients diagnosed with DM2 encompasses various aspects. These include providing education to patients, evaluating the presence of micro- and macrovascular complications, aiming for optimal blood glucose control, reducing cardiovascular and other long-term risk factors, and avoiding medications that may worsen insulin or lipid metabolism abnormalities. Managing inflammation and oxidative stress are essential in the management of DM2 that comprise lifestyle interventions, including regular exercise, a healthy diet, and weight management. Antioxidant-rich foods and/or supplementation with antioxidants may also be beneficial. Additionally, medications targeting inflammation and oxidative stress pathways may be prescribed to alleviate these processes and improve metabolic control in DM2.

The first line of pharmacological treatment is metformin, an oral antidiabetic biguanide agent which has greater anti-inflammatory activity. It should be avoided insulin secretagogues because they are dangerous for frail older adults due the increased risk of hypoglycemia and falls [273]. Moreover, serious hypoglycemia and the concomitant use of warfarin with sulfonylureas or metformin should be taken in consideration for the treatment of older adults [274]

Metformin activates AMP-activated protein kinase (AMPK) pathway, that reduces excessive ROS generation and limits cell apoptosis. Also, it increases signaling through the ROS-mediated PI3K/Akt, AKT/Nrf2 and Nrf2/HO-1 pathways, and markedly elevates the levels of its downstream antioxidants [275,276]. Moreover, metformin may be able to protect cells against H₂O₂-induced ROS by autophagy activation [277]. Some studies indicate that metformin may induce anti-aging transcriptional changes and beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function [278,279], although these data remain controversial. Apart from its hypoglycemic effects, it has been observed to offer further advantages in terms of antioxidant function, weight loss, and the management of several diseases. These include cancer, cardiovascular disorders, and metabolic conditions, encompassing thyroid diseases as well [280].

4.8. Depression

Depression is a severe mental disorder that significantly raises the risk of illness and death, particularly in the later stages of life. Additionally, it diminishes the overall quality of life for both the individuals battling depression and their families. The prevalence of geriatric depression represents a significant challenge to public health, particularly when it occurs alongside chronic medical conditions, often escaping proper diagnosis. It frequently coexists with other health issues, such as DM2 and CVD, synergistically affecting the well-being and disease management of older people [281,282].

The treatment will depend upon the severity, type, and chronicity of the disease. Psychotherapy and pharmacotherapy may be used singly or in combination. For moderate to severe forms of depression, it is better to use pharmacotherapy. However, there are too many drug–drug interactions and greater risk for adverse events.

When dealing with depression in older adults, it is crucial to conduct a thorough review of all the medications the patient is currently taking. This is essential as the medications prescribed for physical ailments can trigger or exacerbate depressive symptoms or the condition itself [283]. Studies conducted have shown significant heterogeneity in the treatment outcomes. However, it was demonstrated that they were effective for late-life major depressive disorder but with less effective results than in younger patients [284].

The primary categories of antidepressant medications include selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors. Among these, SSRIs are the most safe and commonly prescribed class of antidepressants, making them the first-line treatment for older patients due to their limited effects on autonomic system activity and a lower impact on blood pressure [285]. Nevertheless, SSRIs may be associated with falls and osteoporosis [286].

Within SSRIs, the most well-known ones are sertraline, paroxetine, and escitalopram. It's worth noting that paroxetine is linked to cholinergic muscarinic antagonism and robust inhibition of CYP2D6, while sertraline exhibits moderate concerns regarding drug interactions compared to escitalopram. When it comes to choosing an antidepressant for oncological patients, it's a delicate balance between assessing the side effect profile and pharmacokinetics. Drug interactions between antidepressants and antineoplastic drugs (ANs) can potentially compromise the effectiveness of ANs and elevate their toxicity, which has evident implications for prognosis. For most other ANs that rely on CYP 450 3A4 metabolism, caution is advised when administering them concurrently with inhibitors of this isoenzyme, such as sertraline, paroxetine, and fluvoxamine [287].

In laboratory studies, a significant modulation of intracellular ROS levels and GSH levels, as well as changes in antioxidant enzymatic activities and transcriptional profiles of antioxidant genes, were observed in response to sertraline and fluoxetine. These changes led to a delay in cell growth and the induction of oxidative stress [288]. Similarly, other studies have indicated that both fluoxetine and citalopram reduced SOD and MDA levels while increasing ascorbic acid levels after a 12-week treatment in a group of major depressive disorder patients [289]

4.9. Chronic kidney disease

Chronic kidney disease (CKD) is a pathological condition characterized by a decrease in the glomerular filtration rate, closely related to the pathologies previously described, with diabetes and hypertension being the main causes of this condition. Currently, it is one of the main causes of death and morbidity worldwide, where its more advanced stages have a higher prevalence in the elderly [290]. As a consequence of the advanced stages, patients must undergo renal replacement therapies, where hemodialysis corresponds to the main method [291]. However, these patients have a lower life expectancy than people of the same age and sex who are not undergoing hemodialysis (4.3 and 5.3 years less). Furthermore, the median survival on dialysis of elderly patients has been reported to be 1.6–5.4 years shorter than those of patients younger than 45 years [291,292].

Oxidative stress plays a fundamental role in the development and progression of CKD, as it is related to the etiopathogenesis of its causes, as well as by being directly involved in glomerular damage, interstitial fibrosis, inflammation and microvascular dysfunction present in kidney damage [293]. The main sources of ROS in the kidney correspond to the mitochondria and the NOX enzyme [294]. The chronic increase in ROS in the tubular epithelium exposes the tissue to direct cellular damage, but also induces elevations of proinflammatory cytokines such as TGF-B, which promotes the synthesis of collagen fibronectin, and plasminogen activator inhibitor-1, while attenuating activity of extracellular matrix degradation factors in mesangium and endothelial cells [293].

As a result of the above, various biomarkers of oxidative stress have been studied in subjects with CKD. First, in relation to lipid peroxidation, elevated plasma levels of MDA, 8-isoprostanes [295] and thiobarbituric acid reactive substances (TBARS) have been reported in patients with CKD. Also, high levels of 8-hydroxy-20-deoxyguanosine are found as a biomarker of oxidative damage in the leukocyte DNA of patients with CKD [296]. Likewise, urine 8-hydroxy-20-deoxyguanosine and serum MDA levels were significantly higher in diabetic patients with proteinuria [297]. Also, increased levels of protein oxidation, such as carbonylation, nitrotyrosine, advanced oxidation protein products and nonenzymatic advanced glycation end products [298,299].

The management of CKD is based mainly on strict control of blood pressure and glycemia in all patients, including older adults. For this, drugs such as ACE inhibitors or ARBs are the most recommended for hypertension and proteinuria. While the effect on oxidative stress was described in the hypertension section, the antioxidant/oxidant effect has also been reported in CKD [300].

On the other hand, for the management of diabetes in patients with CKD, the use of metformin and SGLT2 inhibitors (SGLT2i) is recommended as first-line hypoglycemic agents. Canaglifozin has been shown to decrease ROS production and cellular damage in cultures of mouse proximal tubular cells by suppressing the increase in renal proximal tubular angiotensinogen mediated by hyperglycemia [301]. Furthermore, it has been reported that the administration of dapagliflozin in cultures of Human proximal tubular cells decreases cytosolic and mitochondrial ROS and prevents cellular damage associated with oxidative stress [302]. Likewise, it has been reported that canagliflozin prevents the increase in MDA, advanced protein oxidation product and nitric oxide mediated by the enzymes iNOS and NOX isoform 4 and in turn increases the activity of SOD and CAT and the levels of reduced glutathione in rats with increased oxidative stress induced by isoprenaline [303]. Empagliflozin has also reported the decrease of superoxide and hydrogen peroxide induced by hyperglycemia in cultures of human proximal tubular epithelial cells, and in turn prevents the activation of inflammatory signaling pathways [304]. On the other hand, recent studies reported that empagliflozin would have antioxidant and anti-renal senescence effects mediated by SIRT1 in a d-galactose-induced aging model in rats [305] and also managed to restore endothelial dysfunction induced by hyperglycemia through the modulation of oxidative stress in human cell cultures [306].

5. Antioxidants treatments for aging related diseases

One way to reduce polypharmacy-related adverse effects may be to incorporate or replace conventional therapies with therapies based on natural antioxidant products, such as ascorbic acid, quercetin, resveratrol or curcumin. These agents act through mechanisms of action different from conventional drugs, have a safe adverse events profile and beneficial effects in various conditions that have oxidative stress as a common pathophysiological pillar, reporting evidence in hypertension, DM2, dyslipidemia, polyneuropathy, cognitive decline, among other pathologies and aging-related conditions with a high prevalence in the elderly. Therefore, its use could allow achieving therapeutic goals at lower doses of standard therapy by enhancing its individual effects with those of antioxidants, avoiding the addition of new drugs to the base therapy, which increases the risk of adverse events associated with polypharmacy or the use of high doses of each drug.

5.1. Vitamin C

One of the most studied antioxidants in various clinical models corresponds to vitamin C, which is a water-soluble molecule that acts as a direct antioxidant as it is a powerful radical scavenger of ROS. In addition, it has other indirect effects on the redox state by recycling vitamin E, reducing NF-κB levels or preventing BH4 oxidation [307]. Furthermore, clinical studies in older adults have reported that oral consumption of vitamin C achieves an increase in antioxidant defenses and a decrease in markers of lipid peroxidation in patients with DM2 [308,309]

Several clinical studies have been carried out to demonstrate its antihypertensive effect, based on the report of an inverse relationship between plasmatic vitamin C levels and blood pressure levels, which could be explained mechanistically by the activity of up- regulation of eNOS and down-regulation of NOX [310]. Furthermore, this is consistent with the improvement in endothelial dysfunction reported in patients with various pathologies [307,311]. Our team conducted a randomized placebo-controlled clinical trial, where it was reported a significant decrease in systolic, diastolic, and mean blood pressure in patients with untreated essential hypertension after daily consumption of 1 g vitamin C and 400 IU of vitamin E orally for 8 weeks, associated with an improvement in oxidative stress, specifically a decrease in MDA and F2-isoprostane levels and an increase in ferric reducing antioxidant power (FRAP) and the GSH/GSSG ratio [312]. However, the subjects enrolled in this study had no other comorbidities and were between 35 and 60 years of age, with a mean of 46 years. On the other hand, another randomized placebo-controlled study reported that after consuming 1 g of vitamin C orally for 6 weeks, the blood pressure response to low-intensity exercise would improve in patients with DM2, obtaining lower systolic and diastolic pressures immediately before and after exercising, added to a decrease in the levels of MDA and F2-isoprostanes in patients supplemented with vitamin C [311]. Likewise, another study reported that the use of oral vitamin C decreases systolic and diastolic blood pressure in patients with hypertension with a mean age of 69 years [313]. Furthermore, a recent systematic review and meta-analysis concluded that vitamin C causes a significant reduction in blood pressure in patients with essential hypertension, even in those subgroups of patients older than 60 years [314]. Furthermore, the use of vitamin C in patients with refractory hypertension has also shown benefits in the elderly patient group, significantly reducing systolic blood pressure after a 6-month administration of 600 mg/day compared to a group of non-elderly patients with refractory hypertension who were also given the same dose of vitamin C [315] (Table 1).

Table 1. Main antioxidant drugs used in age-related diseases and their therapeutic effects in clinical trials that evaluated oxidative stress parameters.

Antioxidant	Disease	Dose	Results	Reference
Vitamin C
	Hypertension	1 g/d orally for 6 weeks	− ↓ MDA and F2-isoprostanes − ↓ SBP and DBP	[311]
		1 g/d plus 400IU/d of vitamin E orally for 8 weeks	− ↓ 8-Isoprostane − ↑ FRAP and GSH/GSSG − ↑ SOD, CAT and GPX − ↓ SBP and DBP	[312]
		600 mg/d orally for 6 months	− ↓ MDA and 8-Isoprostane − ↓ CRP − ↓ SBP	[315]
	DM2	1 g/d orally for 4 months	− ↓ skeletal muscle DCFH oxidation − ↑ΔRd − No statistically differences in oxidative stress parameters − ↓ SBP and DBP	[316]
Vitamin E	Hypertension	400 IU/d/4,5 years	Without significant differences in: − Cardiovascular mortality. − Myocardial infarction − Stroke	[364]
	Hypertension and Cancer	600 IU/d on alternate days	Without significant differences in: − Myocardial infarction − Stroke − Total cancer incidence − Incidence of breast, lung, or colon cancer − Total mortality	[365]
Curcumin
	DM2 NAFLD		− ↓ Blood glucose − ↓ Blood triacylglycerides − ↓ Aspartate aminotransferase − ↓ Alanine aminotransferase − ↓ MDA − ↓ TNF-α − ↓ hs-CRP − ↓ MCP-1	[327]
Resveratrol
	DM2	200 mg/d for 24 weeks	− ↓ Fasting Plasma Glucose − ↓ HbA1c − ↓ Fasting insulin − ↓ HOMA-IR − ↓ MDA − ↓ TNF-α − ↓ hs-CRP − ↓ IL-6	[329]
Quercetin
	Hypertension	150 mg/d for 6 weeks	− ↓ SBP − ↓ HDL − ↓ hs-TNF-α − ↓hs-CRP	[323]
Coenzyme Q10
	Coronary artery disease	150 mg/d orally for 12 weeks	− ↓ MDA − ↑ CAT and SOD activity	[361]
	Hemodialysis	300 mg to 1800 mg	− ↓ Isofurans − No statistically differences in F2-isoprostanes.	[362]
	Hemodialysis	1200 mg/d orally for 4 months	− ↓ F2-isoprostanes − No statistically differences in levels of isofurans, cardiac biomarkers and BP	[363]
NAC
	Peritoneal dialysis	600 mg twice daily orally for 8 weeks	− No statistically differences in oxidative stress biomarkers − ↓ IL-6	[366]
	Rheumatoid arthritis	600 mg twice daily for 12 weeks	− ↓ MDA and NO − ↑ TTG	[337]
			− ↓ NO and FBS − ↑ HDL	[338]
	CKD	1200 mg/d added to ACEI or AT1RA therapy for 8 weeks	− No statistically differences in BP, albuminuria and homocysteine plasma levels	[367]
α-lipoic acid			−
	DM2	600 mg/d orally for 6 months	− No statistically difference in SOD, GPX and 8-isoprostane − ↑ HDL − ↓ AGEs receptors − ↓ markers of inflammation	[349]
	DM2 complicated with ACI	600 mg/d iv for 3 weeks	− ↑ SOD and GPX − ↓ MDA − ↓ NIHSS score, HOMA-IA, blood glucose and blood lipids	[351]
	DM2	600 mg/d plus others compounds* orally for 3 months	− ↑SOD and GPX − ↓ MDA − ↓ blood lipids − ↓ Hs-CRP	[348]
	DM2	400 mg/d orally for 4 weeks	− ↓ d-ROMs − ↑ HDL	[350]
	DM2	300, 600, 900, and 1200 mg/d orally for 6 months	− ↑ F2α-Isoprostanes and 8-OHdG in the placebo, but not in the supplemented group − ↓FBG and HbA1c	[352]
	IGT	600 mg/d iv	− ↓ MDA and 8-iso-prostaglandin − ↓ inflammatory markers − ↓ blood lipids − ↑ adiponectin	[368]
	Overweight or Obese Adults	600 mg/d orally for 24 weeks	− ↑ HMOX1 gene expression − No statistically difference in FRAP. − ↓ F2-isoprostanes − ↓ blood leukocytes, blood thrombocytes and ICAM-1 − ↓BMI and weight − No statistically difference in FPT, FBG, HDL and LDL.	[369]
	CKD	600 mg/d plus 666IUI/d tocopherols orally for 2 months	− No statistically difference in F2-isoprostanes, protein thiols, IL-6 and CRP.	[354]
	CKD	600 mg/d orally for 8 weeks	− No statistically difference in MDA and total antioxidant status levels. − ↓hs-CRP − ↑HDL	[353]
	Hemodialysis patients	600 mg plus 400 UI vitamin E for 2 months	− No statistically difference in MDA and hs-CRP − ↓ IL-6	[370]
	Hemodialysis patients	600 mg/d for 8 weeks orally	− ↑ SOD − No statistically difference in mean levels of albumine, Hb, weight and BMI	[356]
	Hemodialysis on DM patients	600 mg/d for 6 months orally	− ↓ 8-OHdG − ↓ hs-CRP, TNF-α − ↓ urea and BUN − ↑ Hb, serum iron, Tsat. − ↓ FBG, HbA1c, fructosamine,	[357]
	Hemodialysis patients	600 mg/d plus 666IU/d mixed tocopherols orally for 6 months	− No statistically difference in oxidative stress and inflammation biomarkers.	[355]

*600 mg of α-lipoic acid, 165 mg of L-carnosin, 7.5 mg of zinc, and vitamins of group B.

Vitamin C has also presented an improvement in metabolic parameters [309,316–318], where a clinical trial reported that the use of vitamin C for 8 weeks managed to reduce the levels of fast blood glucose and inflammatory parameters, the IL6 and high-sensitivity C-reactive protein (hs-CRP), in a group of patients with hypertension and/or obesity and a mean age of 50.69 years [319]. In addition, Mason et al. reported that supplementation of 1 g/day of vitamin c for 4 months improves postprandial glycaemic control in patients with DM2 and a mean age of 61.8 years, also showing a decrease in F2-isoprostanes and systolic and diastolic pressure by −7 mmHg and −5 mmHg, respectively[318]. Moreover, the use of vitamin C and/or E in men who daily consume metformin has been found to improve insulin resistance and fasting blood glucose levels, with an increase in GSH [317].

However, despite this evidence, the recommendation to use vitamin C as antihypertensive therapy remains inconclusive, so further clinical studies must be performed to elucidate it. In addition, there is a need to carry out clinical studies that evaluate the effects of associating vitamin C with conventional hypertension therapy.

5.2. Polyphenols

Polyphenols are a wide variety of compounds with different subclasses, such as flavonols (as quercetin), flavanones, flavones, isoflavones, anthocyanins, stilbenes (as resveratrol), and curcuminoids (as curcumin), among others [320]. Within the scientific community, it has been suggested that these natural compounds may provide benefits in various areas of health, including effects on the cardiovascular, musculoskeletal, neurological, metabolic systems, as well as in the prevention and treatment of non-communicable diseases and cancer.

A systematic review and meta-analysis reported that quercetin reduces systolic and diastolic BP after analyzing 7 randomized controlled trials (RCTs), suggesting that the effect would be greater in those who received doses higher than 500 mg/day. However, only 1 of the articles included patients with arterial hypertension, another included patients with prehypertension, and all others included subjects without hypertension [321]. Similarly, in another RCT with doses lower than 500 mg/day, overweight or obese patients with prehypertension and stage I hypertension experienced a slight reduction in blood pressure at 24 h with a dose of 162 mg/day compared to the placebo group. However, this dose did not have a significant effect on blood pressure in the overall group [322]. The same effect was observed in an RCT in a population of 93 overweight or obese subjects where a dose of 150 mg/day of quercetin was administered for 6 weeks which led to a decrease in blood pressure in the hypertensive subgroup, in addition to significantly decreasing the plasma concentration of atherogenic oxidized LDL, which positions quercetin as a promising natural antioxidant with cardioprotective properties [323]. Another polyphenol that has shown diverse results in reducing cardiovascular risk is resveratrol. In a review where several RCTs were analyzed, it was found that this antioxidant significantly reduced body weight in obese patients and partially lowered systolic blood pressure, in addition to improving parameters such as fasting glycemia and glycosylated hemoglobin in diabetic patients. However, the range of doses used in the different RCTs varies between 5 and 5000 mg/day and over wide periods (from a couple of days to months) [324]. Importantly, although there is evidence that some natural antioxidants, such as those obtained by consuming berries, do not appear to reduce blood pressure when used as monotherapy [325], evidence suggests that polyphenols may have cardioprotective effects when consumed in a diet rich in them, thanks to the pleiotropic effects generated by the different subclasses of polyphenols [326].

In addition to the cardioprotective effects of antioxidants mentioned above, it is important to highlight the role that these compounds can play in improving the cardiovascular risk profile, being beneficial in the prevention and progression of pathologies such as DM2. In a systematic review focused on the analysis of RCTs it could be seen that curcumin can reduce blood glucose and triglyceride levels, as well as other liver function markers such as the enzyme alanine aminotransferase and aspartate aminotransferase in patients with DM2, concluding that curcumin is beneficial in improving metabolic complications, but that future research is still needed to clearly determine other aspects related to its absorption and bioavailability [327]. In relation to the above, studies conducted with other antioxidants such as resveratrol, have shown beneficial effects on the control of glycosylated hemoglobin (Hb1Ac) and glucose control [328]. Supporting the previous hypothesis, a recent RCT conducted in diabetic patients receiving a daily dose of 200 mg of resveratrol showed that, after 24 weeks of supplementation, a significant reduction in plasma glucose and an increase in the homeostatic insulin resistance model were observed, in addition to a decrease in inflammatory parameters such as hs-CRP and TNF-α. These effects were observed without the presence of side effects, suggesting the possibility that resveratrol supplementation, in combination with oral hypoglycemic agents, may be useful in diabetes therapies [329] (Table 1).

Regarding musculoskeletal health, one of the polyphenols with relative evidence is resveratrol. OA is one of the most common disorders in this area worldwide, in which inflammation plays a major role. In an RCT where 40 g of lyophilized blueberry powder were assigned for 4 months to 33 patients with OA, it was observed that there was a decrease in pain, stiffness, and difficulty in performing daily activities at the end of the study, which was observed despite not observing a decrease in inflammatory parameters such as TNF-α, interleukins, or matrix metalloproteinases [330]. Similarly, in an RCT where resveratrol was used as an adjuvant therapy with meloxicam for patients with OA, this antioxidant significantly improved pain, functional capacity, and associated symptoms compared to placebo, while demonstrating a good safety profile and being well tolerated by patients [331]. It is worth noting that the doses used were more than double those commonly used in the RCTs mentioned in this review (500 mg vs 200 mg per day), which, combined with the therapy's good tolerability, suggests that further studies with higher doses of this antioxidant may yield better results.

Another of the health benefits for which polyphenols stand out are their anticarcinogenic effects. In a review where the effect of various flavonoids on different types of cancer was extensively analyzed, the beneficial effects of these antioxidants on lung, breast, gastric, colorectal, liver, cervical and prostate cancer, among others, could be seen by regulating the inflammatory response and decreasing oxidative stress. One of the flavonoids that stands out in different types of cancer is quercetin, which acts through mechanisms such as decreasing the inflammatory response associated with NF-κB signaling, possibly inducing apoptosis through phosphorylation of AMPK and p53 and blocking pathways such as PI3K and WNT signaling pathway. However, this review concludes that there is still a lack of clinical trials of flavonoids on the use of flavonoids to treat cancer [194]. In the same line and supporting what was mentioned by the previous review, in an RCT of 26 patients with breast cancer who consumed 3 capsules/day (296.4 phenolic compounds per capsule, including curcumin and resveratrol) the presence of metabolites derived from curcuminoids, isoflavones and lignans in malignant breast tissues was analyzed for the first time, which could exert anticancer effects after long-term exposure [332] according to the mechanisms mentioned above.

In addition to the benefits mentioned above, it is important to highlight the potential role that polyphenols may have in benefiting cognitive functions or in the prevention and treatment of neurodegenerative diseases. Although there are clinical trials where it was shown that the consumption of 200 mg of resveratrol on the memory of older adult participants aged 60–79 years for 26 weeks did not achieve significant improvements in aspects such as verbal memory after 6 months [333], there is evidence that the use of higher doses of this antioxidant (up to 1 g orally twice a day) for longer periods (52 weeks) may reduce neuroinflammation and induce adaptive immunity in AD [334]. Furthermore, RCTs have demonstrated that the consumption of curcumin can lead to an elevation in plasma Vitamin E levels and an increase in serum levels of Aβ40. This effect potentially indicates curcumin's capability to disintegrate deposits of this biomarker in the brains of individuals with AD [335]. These findings suggest a potential beneficial role of these antioxidants in therapeutic interventions for this condition. However, additional clinical trials with varying concentrations of these compounds and extended durations are necessary to comprehensively assess the long-term neuroprotective effects.

5.3. N-acetylcysteine

N-acetylcysteine (NAC) is an antioxidant that acts as a radical scavenger and precursor of GSH, which is currently widely used to treat patients with acetaminophen poisoning or as a mucolytic. In a recent RCT, it was reported that supplementation with glycine and NAC in older adults between 61 and and 80 years of age for 16 weeks increases GSH levels in muscle and red blood cells, decreased the levels of TBARS and F2-isoprostanes significantly, until presenting no differences with the levels of young adults with an average age of 25.6 years, who presented a baseline difference of 424% of TBARS and 301% of F2-iso between both groups, decreased systolic blood pressure and improved insulin resistance, endothelial dysfunction and other parameters associated with aging [336].

One of the pathologies where research on the benefits of NAC use has been expanded is rheumatoid arthritis, where it has been reported that the oral administration of 600 mg of NAC twice a day for 3 months in patients with rheumatoid arthritis manages to improve certain parameters of oxidative stress, such as MDA and NO [337] when compared with the placebo group, however, other parameters do not present an improvement, such as the total antioxidant capacity measured in plasma (Table 1) [337,338] and GPX activity [338] do not present significant differences. On the other hand, studies that have evaluated clinical parameters present contradictory results, where Jamali et al. reported a significant reduction of disease activity assessed by DAS28, but Esalatmanesh et al. and Batooei et al. reported that there were no significant differences in this parameter. Morning stiffness decreased significantly with respect to the baseline of the patients, but not when compared with the placebo group [338] (Table 1). Finally, pain severity assessed by visual analog scale, physical performance health assessed by Health Assessment Questionnaire and global health as a parameter of the disease activity evaluated by the same patient presented significant differences with respect to the placebo group [339]. Therefore, the use of NAC in rheumatoid arthritis is debatable, and more studies are needed to demonstrate the true usefulness of this drug.

Also, the use of NAC as an adjuvant treatment to improve cognition in patients with AD has been evaluated. Adair et al. conducted a RCT orally administered 50 mg/kg/day for six months to patients with probable AD, reporting that there were no differences between the control group and placebo in the measurements of oxidative stress parameters (SOD and GPX activity and levels of GSH and TBARS) in peripheral blood, as well as their primary measurements (Mini-Mental State Examination and Activities of Daily Living Scale) did not show significant differences either. However, other parameters such as the Wechsler Memory Scale figure reproduction and the letter fluency task showed significant improvement at 3 and 6 months, respectively, in patients receiving NAC [340]. Other studies have included NAC supplementation in patients with AD but within a multivitamin complex together with other antioxidants [341–343], so the results cannot be directly associated with the use of NAC, which is widely described in the systematic review conducted by Skvarc et al. [344].

5.4. Alpha-Lipoic acid

Alpha-Lipoic acid (ALA) is an endogenous antioxidant derived from octanoic acid, which is found in various foods of animal or vegetable origin. It has a high antioxidant capacity, acting in multiple ways to reduce oxidative stress, among which it has been reported that it acts as a radical scavenger and ionic metal chelator, promotes the synthesis of GSH and recycles other antioxidants such as vitamin C, vitamin E, and coenzyme Q10 (CoQ10) [345]. In addition, this antioxidant has an amphipathic nature, which allows it to act both at the extracellular and intracellular levels. For this reason, in the last years, interest in testing its potential benefits in different pathologies has been increasing, leading to clinical trials in patients with diabetic polyneuropathy, metabolic diseases, cancer, among others [346].

Diabetes mellitus has been one of the pathologies in which various clinical studies have been conducted to test the enhancement of antioxidant defenses through ALA, given the significant role of oxidative stress underlying the disease and its complications described in the previous section [347]. A clinical study reported that the administration of 600 mg/day of ALA in combination with 165 mg of L-carnosine, 7.5 mg of zinc, and B-group vitamins in a dietary supplement for 3 months improved oxidative stress parameters by increasing the activity of SOD and GPX while reducing the levels of MDA [348]. However, another study in which 600 mg/day of ALA was administered orally without other compounds for 6 months in patients with DM2 did not show differences in SOD and GPX activity or levels of 8-isoprostanes when compared to the placebo group [349]. Also, in a study where a daily dose of 400 mg of ALA was administered, a decrease in levels of reactive oxygen metabolites measured by d-ROMs was reported, but no changes were observed in the levels of biological antioxidant potential [350]. On the other hand, the administration of 600 mg/day of ALA intravenously for 3 weeks in patients with DM2 complicated by acute cerebral infarction, achieving an increase in SOD and GPX activity, a decrease in plasma MDA levels, and a reduction in the NIHSS score [351]. Regarding metabolic and inflammatory parameters, blood lipids tend to improve after ALA administration [348–351], along with a reduction in markers of inflammation [348,349,351], blood glucose [351,352], and HbA1c levels [352] in patients with DM2 (Table 1).

Other studies have been conducted to prevent cardiovascular damage in hemodialysis patients or those with CKD through supplementation with ALA. Khabbazi et al. administered 600 mg/day of ALA orally to patients with end-stage CKD, reporting a decrease in hs-CRP levels compared to the placebo group and an increase in HDL cholesterol levels compared to baseline levels. However, there were no significant differences in MDA levels, total antioxidant status, or other lipid profile parameters between the groups [353]. These results are consistent with those reported by other two clinical trial who administered a combination of 600 mg/day of ALA with 666 IU/day of mixed tocopherols for 2 or 6 months, except for the inflammatory parameters, where no significant differences were found [354,355]. Other clinical studies in hemodialysis patients have been conducted, where the administration of 600 mg/day of oral ALA for 8 weeks demonstrated an increase in SOD activity, but no significant differences were observed in mean levels of albumin, hemoglobin, weight, or BMI [356]. In contrast, the administration of the same dose of ALA for 6 months reported a decrease in levels of 8-OHdG, hs-CRP, TNF-α, and metabolic parameters [357] (Table 1).

5.5. Coenzyme Q10

CoQ10 is a lipophilic molecule synthesized within the mitochondria of eukaryotic cells. It plays a crucial role as an electron carrier in the mitochondrial respiratory chain [358]. The prospective use of CoQ10 supplementation in addressing tissue fibrosis, a factor associated with the age-related decline in the functionality of several organs, particularly the heart, is noteworthy. Clinical investigations have shown that CoQ10 supplementation can potentially reduce the extent of cardiovascular fibrosis experienced by older individuals, consequently enhancing cardiovascular performance [359,360]. Several clinical studies have evaluated the use of CoQ10 in metabolic or CVD, however, only a few have reported the effects on oxidative stress. In patients with coronary artery disease, the administration of 150 mg/day of CoQ10 for 12 weeks resulted in decreased levels of MDA and increased activity of the antioxidant enzymes CAT and SOD [361]. Furthermore, the use of CoQ10 in hemodialysis patients decreased isofuran levels in one study, but not F2-isoprostane levels [362], contrary to what was reported in another study where a decrease in F2-isoprostane levels was observed, but not in isofurans, cardiac biomarkers, and BP [363] (Table 1).

ACEI, angiotensin-converting enzyme inhibitors; ACI, acute cerebral infarction; BMI, body mass index; BUN, blood urea nitrogen; CAT, catalase; CKD, chronic kidney disease; DM2, diabetes mellitus type 2; d-ROMs, reactive oxygen metabolites test; FBG, fasting blood glucose; GPX, glutathione peroxidase; HDL, high-density lipoprotein cholesterol; hs-CRP, highly sensitive C-reactive protein; IGT, impaired glucose tolerance; MDA, malondialdehyde; SBP, systolic blood pressure; SOD, superoxide dismutase; Tsat, transferrin saturation; 8-OHdG, 8-hydroxy-2’-deoxyguanosine; ΔRd,delta rate of glucose disappearance.

6. Reductive stress

Reductive stress is a concept that was first mentioned by Albert Wendel, a German biochemist known for his work on the role of glutathione in cellular redox reactions. It is essentially the opposite of oxidative stress and occurs when there is an alteration in redox control and signaling.

As well as oxidative stress, it can have adverse effects on cells and tissues and can affect various signaling pathways, disrupt the balance of ROS, and interfere with normal cellular functions. Excessive levels of reducing agents in cells can lead to reduce mitochondrial function, decrease cellular metabolism, activation of NF-κB pathway and a reduction in the formation of disulfide bonds, which are important for maintaining the structure and function of proteins. This process is particularly relevant in the context of antioxidant therapy, where excessive intake of them can potentially shift the cellular redox balance toward reductive stress, leading to unintended consequences on health and disease [371].

7. Conclusion

In conclusion, aging implies a decrease in biological and metabolic activity, whose main pathophysiological mechanism is the alteration of redox signaling as a result of a decrease in our body's antioxidant defense. This leads to the appearance of various age-related diseases, such as neurodegenerative diseases, CVD, metabolic diseases, cancer, among others. These pathologies demand the use of medicines as the first line of treatment, which causes many older adults to fall into polypharmacy, has hidden costs and dangers, as well as negative effects, and is directly related to the development of frailty, which may compromise even more the body's antioxidant defense systems. This highlights the importance of careful medication management and regular assessment of drug regimens in older adults as well as the potential complementary toxic therapies of cancer for minimizing the adverse effects on oxidative balance.

In this sense, the understanding of the physiopathology of different age-related diseases has led to the development of different therapies based on healthy lifestyles and the consumption of natural antioxidants such as flavonoids, carotenoids, vitamin C, vitamin E, among others, as an option or complement to conventional pharmacological therapies, with the aim of reducing their adverse effects and contributing to the well-being of the older adult population. However, despite having evidence both in support and against the use of certain antioxidants for certain diseases, these therapies still lack the necessary evidence for widespread application in the population. Furthermore, the complexities associated with polypharmacy demand careful consideration when addressing oxidative stress in older adults. In this regard, healthcare professionals must pay special attention to potential drug-induced oxidative stress and pharmacological interactions to ensure optimal antioxidant support and minimize the negative effects of polypharmacy in the aging process. It is imperative to conduct further research to unravel the precise mechanisms underlying the interaction between oxidative stress, antioxidants, and polypharmacy. This will enable the development of personalized strategies aimed at maintaining optimal antioxidant balance in the aging population.

Author contributions

C.R.-S.: Analysis of published articles about oxidative stress-related diseases; V.P-G.: Studies on the state of the art in aging and its relationship with polypharmacy; J.L.-M.: Studies about antioxidants and drugs as a therapy in different diseases; T.G.-F.: Clinical effects of antioxidants in ageing; L.S.: Scientific study rationale; R.R.: Hypothesis design, fund raising. All authors have read and agreed to the published version of the manuscript.

Abbreviations
Aβ,	=	amyloid-β;
ACE,	=	angiotensin-converting enzyme;
AD,	=	Alzheimer’s disease;
AGEs,	=	advanced glycation end products;
AKI,	=	acute kidney injury;
ALA,	=	alpha-Lipoic acid;
AMI,	=	acute myocardial infarction;
AMPK,	=	AMP-activated protein kinase;
ANs,	=	antineoplastic
ARE,	=	antioxidant response elements;
ARBs,	=	angiotensin-2 receptor blockers;
BMI,	=	body mass index;
CAT,	=	catalase;
CKD,	=	chronic kidney disease;
CVD,	=	cardiovascular diseases;
CoQ10,	=	coenzyme Q10;
DM2,	=	type 2 diabetes mellitus;
eNOS,	=	endothelial nitric oxide synthase;
FRAP,	=	ferric reducing antioxidant power;
GFR,	=	glomerular filtration rate;
GLP-1,	=	Glucagon-like peptide-1;
GLUT4,	=	glucose transporter type 4
GPX,	=	glutathione peroxidase;
GSH,	=	gluthatione;
Hb1Ac,	=	glycated hemoglobin;
HDL,	=	high-density lipoprotein;
hs-CRP,	=	high-sensitivity C-reactive protein;
HOMA-IR,	=	Homeostatic Model Assessment of Insulin Resistance;
IL-6,	=	interleukin-6;
IRI,	=	ischemia-reperfusion injury;
LDL,	=	low-density lipoprotein;
MCP-1,	=	Monocyte Chemoattractant Protein 1;
MDA,	=	malondialdehyde;
mPTP,	=	mitochondrial permeability transition pore;
mtDNA,	=	mitochondrial DNA;
NAC,	=	N-acetylcysteine;
NF-κB,	=	Nuclear factor kappa-light-chain-enhancer of activated B cells;
NMDA,	=	N-methyl-D-aspartate;
NSAIDs,	=	nonsteroidal anti-inflammatory drugs;
NO,	=	nitric oxide;
NOS,	=	nitric oxide synthase;
NOX,	=	NADPH oxidase;
Nrf2,	=	nuclear factor erythroid 2;
O2·_,	=	superoxide anion radical;
ONOO−,	=	peroxynitrite;
PARP,	=	poly-ADP-ribose polymerase;
PCI,	=	percutaneous coronary intervention;
PKC,	=	protein kinase C;
PUFAs,	=	polyunsaturated fatty acids;
RAAS,	=	renin-angiotensin-aldosterone system;
RCTs,	=	randomized controlled trials;
ROS,	=	reactive oxygen species;
RNS,	=	reactive nitrogen species;
SOD,	=	superoxide dismutase;
SSRIs,	=	selective serotonin reuptake inhibitors;
TBARS,	=	thiobarbituric acid reactive substances;
OA,	=	osteoarthritis;
8-OHdG,	=	8-hydroxydeoxyguanosine;

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Additional information

Funding

This manuscript was funded by N◦ 1211850 of the Agencia Nacional de Investigación y Desarrollo (ANID). This institution did not participate in the design, literature review, or writing of the manuscript.