Dramatic increases in human lifespan and declining population growth are monumental achievements but these same achievements have also led to many societies today ageing at a faster rate than ever before. Extending healthy lifespan (healthspan) is a key translational challenge in this context. Disease-centric approaches to manage population ageing risk are adding years to life without adding health to these years. The growing consensus that ageing is driven by a limited number of interconnected processes suggests an alternative approach. Instead of viewing each age-dependent disease as the result of an independent chain of events, this approach recognizes that most age-dependent diseases depend on and are driven by a limited set of ageing processes. While the relative importance of each of these processes and the best intervention strategies targeting them are subjects of debate, there is increasing interest in providing preventative intervention options to healthy individuals even before overt age-dependent diseases manifest. Elevated oxidative damage is involved in the pathophysiology of most age-dependent diseases and markers of oxidative damage often increase with age in many organisms. However, correlation is not causation and, sadly, many intervention trials of supposed antioxidants have failed to extend healthspan and to prevent diseases. This does not, however, mean that reactive species (RS) and redox signalling are unimportant. Ultimately, the most effective antioxidants may not turn out to be the best geroprotective drugs, but effective geroprotective interventions might well turn out to also have excellent, if probably indirect, antioxidant efficacy.
Due to declining fertility rates and increasing life expectancy, societies in many developed nations are today ageing at a faster rate than ever before . In societies with traditional age structures, most individuals are young but this also results in population growth at an unsustainable rate. The consequence of today’s more sustainable or even negative growth is an increasing fraction of the population being elderly. By current estimates, there will be 2 billion people over the age of 60 by 2050; the same number that will be in the youngest age category, under the age of 15 .
Age-dependent diseases are, by definition, conditions for which age is a major and often the single most important determinant [2,3]. Individuals over the age of 65 are, for example over ten times more likely to suffer from some form of cancer than before this age . Similar statistics apply to neurodegenerative and cardiovascular diseases (CVD) . Other strongly age-dependent conditions, such as macular degeneration and sarcopenia, while not immediately life-threatening by themselves, limit the quality of life and contribute to increased health care expenditure in ageing populations.
Typically, four out of every five individuals over the age of 65 will have at least one chronic disease, with many suffering from multimorbidity . In ageing populations, the majority of deaths are now due to ‘age-dependent diseases’ such as cancer, CVD, Alzheimer’s disease (AD) and other neurodegenerative diseases . As these age-related conditions are not only debilitating, but also increasingly expensive to treat, extending healthy lifespan (healthspan) is a key translational challenge for biomedical science today [3,6–8], with significant efforts on ageing and age-dependent diseases underway around the world.
While the stated aim is to address the challenges of population ageing, such efforts are too often focused predominantly on developing new therapies for age-dependent diseases or on tools and infrastructure for ‘managing’ age-dependent decline. A major reason for the predominance of this approach is the medical ethics dictum ‘Primum non nocere’ (first, do no harm). This means that diseases are treated, but for long-term preventative interventions, the evidence that benefits truly outweighs risks is often hard to provide in a timely manner to the sceptics. One example of this problem is the criticism that some anti-obesity campaigns have received because of the claim that a negative portrayal of obesity may stigmatize obese patients and may harm their self-confidence . Current clinical care of the elderly is generally focused on initiating intervention upon diagnosis of an actual pathology or disease, instead of developing strategies for early prevention of age-dependent diseases.
One major problem with this disease-centric approach, however, is that tools for better management of age-dependent conditions, e.g. assistive technologies and medical interventions designed to control or ameliorate the consequences of progressive age-dependent diseases, while effective in improving quality of life and extending survival, do not necessarily result in increased healthspan [3,6,8,10–12]. Furthermore, as humans age, they are increasingly less likely to suffer from only a single, isolated disease but are instead at an increased risk of developing additional, independent or secondary age-related diseases. There is, therefore, a risk of disease-centric interventions exchanging or compounding one disease with another. This, paradoxically, means that success in managing some age-dependent diseases may have the unintended consequence of actually expanding average morbidity in the population, which in turn will increase the cost of healthcare by adding years to life but not adding health to those years [6,8,10–13].
Given these concerns, it is worth asking how successful we have been in translating progress in the biomedical sciences into increased healthspan. While the answer to this question depends on the measures of health and disease that are used (and on the specific cohort considered), it is clear that not all of the years added to human lifespan are healthy and that the current disease-centric approach alone may not be the most effective way to deliver the desired extension of healthspan to ageng populations [6,8,10–12,14].
Prevention rather than treatment: lifestyle and healthspan
An alternative (or complementary) approach to the traditional disease-centric approach outlined above, is to extend healthspan through preventing or delaying age-dependent diseases by targeting healthy individuals for preventative interventions before overt age-dependent diseases manifest. By aiming to preserve general function and performance (ability of self-care and contribution to society) before age-dependent decline manifests as disease, this approach prioritizes healthspan and disease prevention over mere survival or lifespan. A commonly explored approach in this context is the modification of lifestyle and diet. There is no question that diet and exercise play an important role in modulating the risk of developing many age-dependent diseases. A diet rich in fruits and vegetables, for example has been shown to significantly reduce the risk of developing CVD, of having a stroke and to decrease the risk of some (but not all) forms of cancer . In fact, demographic studies suggest that higher consumption of fruits and vegetables is associated with lower all-cause mortality [15–17] and may even promote cognitive ability and protect ageing humans from age-dependent cognitive decline . Conversely, obesity and lack of physical activity are known to promote many age-dependent diseases. Especially, a body mass index (BMI) in the very high (BMI >35 kg/m2) or morbidly obese category (BMI >40 kg/m2) has been shown to increase overall morbidity and mortality and elevate the risk of most age-dependent diseases, including CVD , diabetes/metabolic diseases, some cancers and possibly even of neurodegeneration [20–23]. Despite these facts being widely known and publicized, populations appear to be heading toward obesity as there has been a worldwide increase in obesity, often referred to as the ‘global obesity epidemic’ . This trend unfortunately compounds the challenges of populations ageing in many countries.
There can be no doubt that improving ones’ diet, losing weight and increasing exercise improve ones’ chance of ageing successfully. However, when deciding on how to invest finite public resources to best address the challenges of population ageing, another question needs to be asked. Namely, how effective are available measures to modify individual behaviour on a societal level? Here the answer is more complicated and the outlook appears less promising . Even though information on the negative effects of obesity has been widely and publicly available for decades and despite significant worldwide efforts ranging from health promotion and information campaigns to targeted health education programmes and even economic incentives, there is little compelling evidence that we are succeeding in stemming the global obesity epidemic [24–27]. Sadly, even some healthcare professionals are becoming more obese at a rate similar to that in the general population . Similarly, the benefits of a diet rich in fruits and vegetables are well known and publicised, but changing dietary habits is hard. For example, a nationwide information campaign called ‘5-a-day’ in the U.K. was considered partially successful, having increased daily fruit and vegetable consumption by an estimated 0.3 portions (to approximately four portions a day) between 2002 and 2006 [25,29], but more recent data suggest that some of even these modest gains have since been lost [29,30].
Given that there are clear and well-known benefits to a healthy diet, weight loss and exercise, but the changes in these areas are hard to implement individually and even harder to impose on the population at large, it is tempting to ask if some of the benefits of a healthy diet and lifestyle could be made available more easily and cost-effectively. Can we, as it were, have our cake and eat it too?
As health-promoting diets rich in fruits and vegetables are also rich in compounds commonly considered ‘antioxidants’, might it be possible to identify and extract these active ingredients of a healthy diet and make them available in pill form?
An antioxidant can be defined as any substance that delays, prevents or removes oxidative damage to a target molecule . Importantly, this implies that antioxidant efficacy can only be meaningfully defined relative to a particular type of target molecule and oxidative damage. Oxidative damage is the biomolecular damage caused by attack of reactive species (RS) upon the constituents of living organisms . RS are chemically reactive molecules that can be generated in vivo. RS are commonly produced as unintentional side products during normal metabolism but can also be produced by dedicated pathways to serve useful purposes, including signalling molecules (reviewed in ). One class of RS are the oxygen-containing reactive oxygen species (ROS). ROS include hydrogen peroxide (H2O2) and several oxygen free radicals, that is, species that contain unpaired electrons on the oxygen atom. Superoxide (O2•−) is an oxygen free radical and the precursor for many other ROS species in vivo. O2•− is typically produced in the mitochondria by one-electron reduction, when electrons leak from the electron transfer chain’s electron carriers to molecular oxygen. O2•− is a charged species and therefore cannot pass through the mitochondrial membrane. However, dismutation of O2•− yields H2O2, which is neutral and can diffuse through mitochondrial and other membranes. Complex antioxidant defence systems have evolved to quickly remove most RS, including O2•− and H2O2. However, no detoxification system is perfect and so detoxification is never completely successful. Oxidative damage to DNA, lipids and proteins occurs at low levels but is detectable in aerobes. Oxidative stress has been defined as “an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signalling and control and/or molecular damage” . Oxidative stress and elevated oxidative damage, while often not a cause, is involved in the pathophysiology of most age-dependent diseases (reviewed in [31,34]) and markers of oxidative damage have been reported to increase with age in many organisms [31,34]. Expectations were that suitable antioxidant regimes might be found to scavenge all manner of RS, reduce oxidative damage, decrease disease incidence and even slow down the global ageing rate. This idea encouraged a multimillion-dollar industry of dietary supplements culminating in the ‘mega-antioxidant supplements’ of the 1980s and 1990s; still widely consumed today. There are, however, several problems with this approach. First, it is far from clear that the benefits of a healthy diet are mainly due to its antioxidant content. Fruits and vegetables contain many biologically active compounds, including polyphenols and terpenoids that may or may not primarily act as antioxidants in vivo [31,34–37]. Another key observation is that isolated antioxidants or extracts in in vivo intervention studies often fail to cause consistent reductions in markers of oxidative damage [31,34].
Elderly humans are at a higher risk of malnutrition and there may be some benefits to ensure adequate supply of key compounds such as vitamins. For example, the elderly may require more vitamin C in their diet than the young, possibly due to decline in its uptake . However, beyond moderate benefits of correcting deficiencies, the evidence supporting antioxidant supplementation to modulate ageing and prevent diseases is weak at best. Sadly, many intervention trials of supposed antioxidants have failed to prevent or delay age-dependent diseases [31,34,39–41].
The view that RS are ‘bad’ and, consequently that antioxidants must be ‘good’ is overly simplistic. There is growing evidence that RS and even certain forms of oxidative damage play a role in normal physiology through redox signalling and damage-mediated feedback [31,42,43]. Moreover, redox signalling, compensation and feedback can be complex [44–50] and so are the interactions between dietary components, stressors and ‘antioxidants’ [51,52], questioning the idea that larger amounts of a single (or a few) putative antioxidant compounds might replicate, let alone exceed, the benefits of a balanced diet. In biology (as in life), more is typically not better and might be even harmful when it comes to specific antioxidant compounds [34,39,40,51,53–56].
Prevention rather than treatment: the need for therapies that increase healthspan
So, is general advice on healthy diet, more exercise, weight loss and health drives aimed at smoking secession and stress reduction really the best we can do? Hopefully not, but it has been suggested that to develop new healthspan extending interventions, a paradigm shift in the way we think about and treat ageing is required [3,7,8,14]. Instead of viewing each age-dependent disease as a result of an independent chain of events, we should recognize that most age-dependent diseases depend on biological age. Most importantly, their aetiology is intricately linked to the ageing process itself [3,7,8,14]. For instance, vascular damage with time is a common contributor to stroke, dementia and multiple other diseases and is elevated in diabetes .
We already have one example of a prevention-centric approach paying dividends in CVD prevention. The prevalence of hypercholesterolaemia, especially in elevated low density lipoprotein (LDL) levels, increases with age and, together with high blood pressure, this is a major risk factor in the development of CVD. Prescription of statins and blood pressure modifying medication decreases the incidence of adverse events in patients with existing CVD or that are at the risk of CVD-related adverse events . The prescription of preventative drugs especially in patients only at the risk of developing CVD augurs a paradigm shift in treatment where drug interventions can be used on relatively healthy individuals in order to prevent possible future diseases.
This is a key change in approach and could be extended to not obviously at risk individuals as it is clear that the majority of CVD events (e.g. heart attacks, strokes) occur in ageing subjects who had not been previously identified as high risk . Indeed, lowering CVD risk associated biomarkers such as LDL cholesterol has been shown to be beneficial, even when their baseline levels are considered to be within age-specific normal ranges [58,60]. The fact that modification of these parameters can be beneficial even if initial values are not ‘abnormal’ suggests that the distinction between pathologically abnormal values and ‘normal’ age-dependent changes is not well understood and may not, in fact, be meaningful in the first place. Preventative use of statins is an example where a detailed understanding of both ‘normal’ ageing changes and disease risk associated biomarkers has resulted in pharmacological interventions that can be applied to target what would previously have been considered to be normal ageing changes, with real benefits in terms of healthspan and disease prevention .
Recent studies have found an unexpected decrease in the age-specific risk of suffering from dementia over the last decades [62–65]. What this means is that, in the same age-groups, significantly fewer individuals develop dementia today than would be expected from previous cohorts. This ‘missing’ dementia effect occurs even though, compared to the earlier cohorts, certain risk factors including prevalence of diabetes, hypertension and obesity are actually higher in the more recent cohorts [62,64]. A contributing factor appears to be the protective effect of education, with the more recent cohorts tending to have received more formal education. However, education alone is probably not sufficient to explain the decline in dementia . One intriguing suggestion is that the reduction in dementia is a side effect of better managing the consequences of diabetes and obesity, e.g. by better controlling cholesterol and the consequences of diabetes and related risk factors [62,64,66]. Interestingly, inhibition of cholesterol synthesis by statins appears to reduce the risk of AD, possibly providing a link between CVD prevention and the reduction in dementia [67,68].
Of course, any pharmacological agent that is efficacious is likely to be associated with side effects and risks. A key challenge for any preventative intervention strategy, especially long-term pharmacological interventions, is to ensure that the benefit of intervening outweighs the cumulative risk of side effects and complications. Statins have been associated with a number of side effects including muscle pain, digestive complaints and compromised cognitive performance. However, a recent large meta-analysis found that compared to placebo controls, statin treatment was not associated with increased risk of withdrawal due to adverse effects , suggesting that in the majority of individuals these side effects are relatively manageable. However, there have also been concerns that statin use might sometimes result in more serious, potentially life-threatening, adverse events such as new-onset diabetes, cancer, rhabdomyolysis, myopathy and liver damage [69,70]. However, in most cases, concerns regarding these potentially serious adverse outcomes have not been confirmed, with several large studies finding no evidence supporting a statistically significant association between statin intake and these outcomes, at least for the older and better understood low potency statins [69,70]. In summary, the current evidence suggests that benefits of moderate/low potency statins are associated with lower CVD and all-cause mortality and that their use likely outweighs the risks in the majority of individuals, even those not at extremely high risk of CVD.
Do RS and oxidative damage matter in this context? Hypercholesterolaemia itself is associated with increased oxidative damage [67,68,71]. Oxidized LDL (oxLDL), in particular, plays a complex role in the progression of atherosclerosis, although whether RS-mediated, non-enzymatic oxidation of LDL is causative in CVD remains unclear [31,72]. These observations have resulted in several large intervention trials using compounds such as α-tocopherol, selected with the intent of reducing oxidative lipid damage to prevent progression of atherosclerosis and CVD. Despite early promising results, most of these trials have been disappointing [31,40,41,73–75]. Why have so many large trials of ‘antioxidants’ failed to deliver on their initial promise if oxidative damage plays an important role in the aetiology of CVD? It is far from clear if treatment with compounds such as α-tocopherol actually resulted in a significant reduction in oxidative damage at the right target because large intervention studies, sadly, rarely involve careful determination of biomarkers of oxidative damage to demonstrate efficacy of the intervention [31,34].
Although specific antioxidant treatments have failed, control of cholesterol using statins is associated with not only the reduction in the progression of atherosclerosis and CVD but also with the reduction in oxidative damage [76,77]. While controlling, hypercholesterolaemia itself might result in reduced oxidative damage, there is growing evidence that statins have additional indirect antioxidant effects, possibly by acting on ROS-generating NADPH oxidase enzymes [67,76,78].
Whether or not these antioxidant effects contribute to the disease-prevention efficacy of statins remain to be elucidated. RS and oxidative damage are involved in most if not all age-dependent diseases, but this damage occurs as a part of a complex stress response and redox signalling network. Oxidative damage accumulation is only one aspect of the dysregulation of this network and is only one aspect of a wider network of interconnected detrimental changes that occur during ageing. Any direct antioxidant interventions against age-dependent diseases will require a thorough understanding of the type and role of oxidative damage in their pathophysiology (if any) and the development of appropriate biomarkers to evaluate primary efficacy (reduction in oxidative damage).
However, markers of oxidative damage to biological macromolecules, including protein, lipid and DNA have been widely reported to increase, although typically only modestly, with age in many species, including humans [79–88]. This increase in damage burden might be explained by increased RS production, decreased antioxidant defences, reduced repair and removal of oxidatively modified molecules or a combination of these factors.
There is evidence, mainly from model organisms, for an age-dependent decrease in the function of some but not all antioxidant defence systems [89–91]. GSH/GSSG ratios, in particular, decrease with age [89,91,92]. However, the most consistent age-dependent change contributing to oxidative damage accumulation is a pronounced blunting in the response to homoeodynamic challenges and insults, including, to oxidative stress with age [79,93–96].
One consequence of ageing is an age-dependent decline in the rate of damage removal. For example, autophagy and proteasome activity both become less efficient with age [97–99], thereby facilitating accumulation and aggregation of misfolded protein, especially in brain [93,95,100]. This suggests that interventions which increase proteasome function or improve autophagy might be promising candidates for anti-ageing agents [101,102].
An important concept in this context is hormesis, a paradoxically beneficial response to damaging stressors when experienced at low levels . Such paradoxical benefits derive from physiological responses to mild stress, including activation of stress response pathways. Exposure to low levels of pro-oxidants such as RS-generating poisons can extend lifespan and healthspan in model organisms, sometimes also while elevating oxidative damage to some target molecules [104–106]. Hormetic rather than in vivo antioxidant efficacy may, in fact, explain health benefits of some dietary-derived ‘antioxidants’, such as flavonoids and other polyphenols such as resveratrol [107,108]. Exercise increases RS generation in muscle and possibly elsewhere in the body and the consequent adaptive response contributes to its health benefits, suggesting that exercise in moderation is a good antioxidant [42,109–111].
This complexity should not be surprising. Since life first emerged, free radicals, other RS and oxidative modifications of biological molecules have likely to be integral and consequences of some of the most basic processes of life. Organisms have thus evolved complex redox signalling and homoeodynamic mechanisms to protect themselves from, respond to and make use of these RS and oxidative modifications. The answer to the question regarding the role of RS in biology should not be expected to be simpler than the answer to the question regarding the role of metabolism in the same context.
There is a growing consensus that ageing is driven by a limited number of detrimental processes [112,113]. Key processes are thought to be (in no particular order): genomic instability, telomere attrition, mitochondrial dysfunction and hypometabolism, cellular senescence, epigenetic alteration, loss of proteostasis, deregulation of nutrition sensing, stem cell exhaustion, altered intercellular communication (including redox signalling) and possibly dysregulation of inflammation (inflammaging) [31,112–114]. RS are involved in one way or another in all these processes. While the relative importance of these processes and the best intervention strategies are subjects of debate, these mechanisms are now objects of intense research efforts and intervention strategies are being explored for many of them [7,112]. Targeted antioxidant interventions may yet turn out to be one weapon in this arsenal [115,116], but recently there has also been excitement around repurposing of existing human drugs for healthspan-extending interventions.
Metformin (N,N-Dimethylimidodicarbonimidic diamide) is commonly used for the treatment of type 2 diabetes because it suppresses hepatic gluconeogenesis. There is some evidence that diabetics treated with metformin have a reduced risk of cancer  and a retrospective observational study of more than 180000 diabetic patients and matched non-diabetic controls found that patients with type 2 diabetes treated with metformin alone had longer survival (lower mortality) than even non-diabetic control individuals . Transcriptional profiling in mice suggests that metformin might mimic caloric restriction [119,120]. Lifespan and healthspan benefits have since been confirmed in nematodes, flies and mice [121–123]. Based on this cumulative evidence, a large, double blind, placebo-controlled study of metformin in 3000 healthy volunteers has recently been approved. This ‘Targeting Aging with Metformin’ (TAME) trial will investigate if treating healthy (non-diabetic) elderly individuals with metformin can delay the onset of multimorbidities and increase thew healthspan. This is the first FDA-approved trial where prevention of generalized age-dependent decline rather than any specific pathology or disease is the major goal. While metformin is the drug currently closest to being clinically tested in this way, other compounds, such as rapamycin, have also recently generated much interest as potential geroprotectors . Rapamycin inhibits signalling through the TOR nutrition sensing pathway and lifespan extension has been confirmed in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster and mice [124–127] although, due to its immunosuppressive action, there are concerns with any preventative use of rapamycin in healthy humans. Both metformin and rapamycin appear to confer benefits by mimicking aspects of caloric restriction, which may be useful since it is not entirely clear how effective actual caloric restriction will be in extending lifespan and healthspan in humans .
Metformin treatment induces endogenous stress response pathways in model organisms and reduces several markers of oxidative damage [121,122,129]. Similarly, rapamycin activates autophagy, a process contributing to the clearance of damaged macromolecules (including oxidized ones) and reduces markers of oxidative stress in aged mice . Such oxidative damage modulation may or may not contribute to any benefits of these compounds.
Debates about ageing theories in the past were often focused on the relative importance of different processes or forms of damage [31,131]. There is now a growing consensus that, on a molecular and cellular level, there is not a single cause of ageing but that, ageing is driven by a (limited) number of detrimental physiological and damage-accumulation processes [6,7,112,113,132,133]. With this consensus comes, the realization that ageing processes are highly interconnected and interdependent. Thus, it is not surprising that for instance statins, originally developed to narrowly target a specific problem (hypercholesterolaemia), also impact oxidative damage and systemic inflammation.
As expected, views differ regarding the relative importance of fundamental ageing processes and regarding the potential for, and the best way to translate knowledge about ageing into effective interventions [6,7,14,113,132–135]. Whatever effective interventions (if any) eventually emerge can be expected to be complementary or even synergistic. The most effective antioxidants may not turn out to be the best geroprotective drugs, but effective geroprotective interventions might well turn out to also have excellent antioxidant efficacy e.g. by up-regulating endogenous defence or damage repair mechanisms. Correlation, of course, is not causation and this does not mean that such antioxidant action is necessarily causative in any geroprotective efficacy .
Dramatic increases in lifespan and declining population growth are monumental human achievements but these same achievements have also led to new challenges, not least population ageing. There is an urgent need to translate our growing understanding of ageing into interventions by targeting ageing processes to delay age-dependent disease and to extend human healthspan. This approach carries great promise but for these opportunities to be realized, concerted action will be required from the scientific community, legislators, funding agencies and industry [2,6–8,112,136]. This approach may help to ameliorate the consequences of population ageing by increasing healthspan and reducing medical expenditures in countries with ageing populations . This is not to say that attempts to curb obesity, improving diet and exercise habits should not be pursued vigorously. They must be, but these efforts should be supplemented with pharmacological approaches that can delay the onset of age-related diseases in otherwise healthy individuals.
Elevated oxidative damage is involved in the pathophysiology of most age-dependent diseases and markers of oxidative damage often increases with age in many organisms. However, many intervention trials of supposed antioxidants have failed to extend healthspan and prevent diseases.
Reasons why this is the case include the failure of antioxidants to decrease oxidative damage; alternative approaches can involve the use of mild pro-oxidants.
Ultimately, the most effective antioxidants may not turn out to be the best geroprotective drugs, but effective geroprotective interventions might well turn out to also have excellent, if probably indirect, antioxidant efficacy.
This work is supported by the Tan Chin Tuan family through its Centennial Professorship Funds ; and the Ministry of Education Singapore for funding support [grant number MOE2014-T2-2-120 (to J.G.)].
The authors declare that there are no competing interests associated with the manuscript.