The rapid increase in our understanding of the molecular mechanisms that underlie ageing has created new opportunities to intervene in the ageing process. Two notable findings have emerged from these early studies. First, the number of genes that can extend lifespan is much larger than expected, which suggests a much higher level of plasticity in the ageing process than expected. Second, genes that control ageing—which define cellular pathways such as the TOR and insulin signalling pathways—are remarkably conserved in yeast, worms, fruit flies and humans. The conservation of these pathways across wide evolutionary distances and the fact that targeting these pathways in model organisms increases both lifespan and healthspan has brought to the fore the idea of interventions in humans.

Rapidly ageing societies across the world are seeing an increasing healthcare burden attributable to both morbidity and cost of age-related diseases, such as heart disease, stroke, cancer, neurodegeneration, osteoarthritis and macular degeneration. However, current medical care is highly segmented as well as organ- and disease-based, and ignores the fact that age and the ageing process are the strongest risk factor for each of these diseases. According to the concept of geroscience, targeting conserved ageing pathways is anticipated to protect against multiple diseases and represents a different approach to tackling the rapidly growing burden of diseases worldwide (Table 1).

Table 1 Interventions to increase healthspan and/or lifespan Full size table

Using geroscience to treat age-related disease

The concept of geroscience predicts that conserved ageing pathways are part of the pathophysiology of many age-related conditions and diseases (Fig. 2). For example, multimorbidity is seen as the multisystem expression of an advanced stage of ageing rather than a coincidence of unrelated diseases117. Targeting conserved ageing pathways should, therefore, prevent or ameliorate multiple clinical problems. This hypothesis remains to be tested in clinical trials, but is supported by several lines of evidence. A wide range of animal models of specific diseases can be affected by manipulating a single ageing mechanism (such as NAD+)118 or senescent cells95 in the laboratory. Rates of individual age-related diseases and of multimorbidity increase nonlinearly with age, and the rate of acquiring new chronic diseases may be higher in people who have an existing chronic disease119.

Fig. 2: The concept of geroscience and its approach to age-related disease. Environmental and genetic factors exert influences on a number of key cellular processes and pathways, which have recently been defined as the hallmarks of ageing193. Many of these pathways contribute to the creation of a chronic inflammatory stage and to ageing. These in turn increase the risk for chronic diseases of ageing together with disease-specific risk factors (for example, cholesterol level and high-blood pressure can lead to cardiovascular diseases such as stroke and myocardial infarction). Full size image

Certain populations, such as people who live with HIV or are homeless, show an early onset of a wide range of age-related chronic diseases and geriatric syndromes that are not necessarily related to their specific disease risks120,121. A classic statistical analysis of human mortality showed that even curing an entire category of chronic disease, such as all types of cancer or cardiovascular diseases, would only modestly increase life expectancy owing to the expected mortality from other chronic diseases122. Conversely, humans with extreme longevity who presumably have favourable ageing mechanisms show delayed onset of most major chronic diseases123.

In clinical care, multimorbidity is increasingly viewed as an entity unto itself that requires a specific integrative management plan124, as intensive but uncoordinated treatment of individual diseases can give rise to the harmful syndrome of polypharmacy125. Frailty measures are the most widely used clinical assessments for quantifying the stage of ageing126,127, and these clinical biomarkers of ageing predict mortality while awaiting liver transplant128, complications of surgery129 and whether the pathology of Alzheimer’s disease manifests as clinical dementia130. Taken together, experimental data from preclinical models, epidemiological patterns of age-related conditions and the power of non-disease-specific clinical ageing assessments such as frailty to predict risk and mortality in diverse contexts all suggest that intervening in mechanisms of ageing could have broad clinical benefit.

Challenges ahead

However, to move from simple organisms to humans several key difficulties need to be overcome, as discussed below. First, it is already clear from the study of model systems that interventions that are beneficial in a given genetic environment might not work in another. For example, analyses of dietary restriction in multiple recombinant inbred mice strains found both an increase and a decrease in lifespan, which was dependent on the strain131. Similar results have been obtained using more than 150 strains of flies132. The molecular basis for these differences in response to what had been assumed to be a universally beneficial intervention has not been established. Future studies in invertebrates such as yeast, worms and flies hold promise for systematically explaining the genetic basis of lifespan extension by dietary restriction.

The human population is also characterized by a large genetic heterogeneity that has a critical role in disease susceptibility, lifespan and the response to drugs of an individual. This heterogeneity is the basis for the current field of precision medicine, which aims to identify critical genetic determinants of disease and to customize interventions and treatments to unique genetic variants. In the future, the field of precision medicine and geroscience will have to interact closely. As discussed above, FOXO3 is related to the DAF–insulin pathway, and unique polymorphisms in FOXO3 are found in centenarians around the world17. Furthermore, the APOE gene is involved in cholesterol metabolism, and unique alleles are associated with longevity and a lower risk of developing Alzheimer’s disease133,134. Many additional genes135, such as SIRT6136, are now known to be associated with human longevity.

Just as several animal studies have challenged the universality of the benefits of dietary restriction137,138,139, it is likely that pharmacological interventions will work with different success in distinct humans, owing to the natural genetic variation in the population138. As in mice, it has been hypothesized that selective pressures on the response to nutrient availability may vary across different human populations, resulting in genetic differences that may influence diabetes and obesity140. Furthermore, most of the interventions have arisen from research to show protection against ageing in animals. Thus, it is possible that humans that have optimized their nutrition and exercise are unlikely to derive much benefit from these interventions. Future studies on tailoring interventions based on personalized medicine approaches are likely to be most successful in deriving the most benefit from these interventions.

Additionally, it is clear that studies in mice are not always predictive for humans. Many important discoveries in mice have been translated successfully in humans, but many others have not. This can be due to intrinsic biological differences between mice and humans. In addition, the complexity of biology and the multiplicity of recognized and unrecognized variables that affect biological phenotypes have caused reproducibility problems between different laboratories that study the same organisms, not only in studies of mice but also other model systems141.

Although there are many examples of a connection between long lifespan and increased healthspan, more-recent studies in mice142,143, flies132 and worms144,145,146 have questioned the assumption that lifespan extension is always accompanied by an increase in healthspan. Future studies will need to address the effects of interventions on both of these aspects before attempting to translate these interventions into the treatment of human patients.

Drugs undergoing clinical trials

Both drugs that are being developed to target ageing and some drugs that are commonly used behave as geroprotectors in animal models. The multicentre Intervention Testing Program (ITP), which is supported by the National Institute for Ageing, has identified five drugs that reproducibly increase lifespan in genetically heterogenous mice147, including rapamycin, acarbose, nordihydroguaiaretic acid, 17-α-oestradiol and aspirin147. Some of these drugs also improve healthspan measures in some tissues of animal models148,149,150. Drugs found in other studies to extend rodent lifespan include metformin151 (although it did not repeat in the ITP at the same dose), drugs targeting the angiotensin-converting enzyme and the aldosterone receptor, and the sirtuin activators SRT2104152 and SRT1720153. Further work will be necessary to validate that these drugs act as true geroprotectors in model organisms.

A key question is how these interventions will be tested and eventually used clinically in humans. Geroscience predicts that ageing therapies will ameliorate or prevent several age-related diseases and conditions simultaneously. Clinical trials to test this hypothesis should therefore use clinical outcomes that inherently depend on multiple age-related diseases or conditions. Examples include multimorbidity, or the combination of several age-related chronic diseases; the multifactorial geriatric syndromes such as frailty or delirium; or resilience to health stressors such as surgery or infection154. Multimorbidity and frailty are also widely incorporated into measures of age-related risk that inform clinical decision-making155. Other examples of such measures that could be useful trial outcomes include grip strength, gait speed156, timed-up-and-go and activities of daily living.

These clinical measures of ageing could be useful for selecting patients at higher age-related risk to receive interventions. For example, the risk of multimorbidity increases steeply with age119; however, developing one chronic disease increases the risk of developing another by several fold157. How early or late in the ageing process interventions can be effective remains to be seen, although animal studies of drugs and human studies of exercise provide some reassurance that the window of opportunity extends quite late in life. At least five major classes of drugs are currently being tested in humans for their geroprotective potential.

Metformin

Metformin is a widely prescribed antidiabetic drug that has been found to target several molecular mechanisms of ageing158. A retrospective analysis of patients with diabetes who received metformin showed increased lifespan in comparison to individuals without diabetes159. In randomized trials, metformin prevented the onset of diabetes, improved cardiovascular risk factors and reduced mortality160,161. Epidemiological studies have suggested that metformin use might also reduce the incidence of cancer and neurodegenerative disease158. These data underpin the proposed Targeting Aging with MEtformin (TAME) study, a large randomized controlled trial of metformin given to 65- to 80-year-old individuals without diabetes who are at high risk for the development of chronic diseases of ageing. The primary outcome of TAME is a composite of death or new major age-related chronic diseases, including cardiovascular disease, cancer and dementia. Other outcomes include geriatric measures such as mobility, independence in activities of daily living and cognitive function162.

Rapamycin analogues

The compound identified by the ITP that has perhaps the most reproducible effects on lifespan is rapamycin. Rapamycin inhibits the TOR pathway, extends the lifespan of yeast and flies and increases mean and maximum lifespan in mice from multiple genetic backgrounds163,164,165. These basic research data led to a unique clinical trial that studied the effects of rapamycin on heart function, cognition, cancer and lifespan in household companion dogs as a preclinical model166. Rapamycin (also known as sirolimus) and its analogue everolimus are approved for clinical use as immunosuppressants in solid organ transplantation. Healthy older adults given a non-immunosuppressive dose of everolimus for six weeks showed an improved immunological response to influenza vaccination19. A subsequent clinical trial found that six weeks of low-dose everolimus plus a second TOR inhibitor improved vaccine response and, provocatively, reduced infection rates by over a third during the subsequent nine months167. These were two of the first examples of clinical trials that target a syndrome of ageing—immunosenescence—with a drug that targets the mechanisms of ageing.

Senolytics

As discussed above, senolytic drugs—drugs that selectively target and eliminate senescent cells—have showed great geroprotective potential in animal models95. Some of these drugs are natural products96,97, whereas others are synthetic small molecules90,98,99. A growing number of biotechnology companies and research laboratories are developing new or repurposed senolytics that have just begun to be tested for safety in humans, with no results—thus far—regarding efficacy.

Sirtuin activators

Sirtuin-activating compounds (STACs) enhance sirtuin activity and increase healthspan in mice and non-human primates168. However, mixed conclusions have been observed in clinical trials. Resveratrol (a natural STAC) and SRT1720 (an early synthetic STAC) have shown promising results in preclinical trials but failed in clinical trials, owing to low bioavailability, potency and limited target specificity169. The most promising synthetic STAC so far is SRT2104, a highly specific SIRT1 activator; the compound has completed several small clinical studies of effects on cardiovascular and metabolic markers, including in type 2 diabetes, cigarette smokers and the elderly, with larger trials underway118.

NAD+ precursors

NAD+ precursors such as nicotinamide riboside and nicotinamide mononucleotide aim to supplement the age-associated decrease in cellular NAD levels69. In animal models, both precursors have shown geroprotective activity against a number of ageing-associated diseases. Several companies are currently selling nicotinamide riboside and nicotinamide mononucleotide as supplements online. Although these supplements increase NAD levels in humans170, no efficacy or geroprotective effects for humans have been demonstrated thus far.

Exercise improves healthspan

Although much hope and investment are currently focused on drug development, it is important to note that exercise behaves as a true and effective geroprotector. In the absence of suitable treatments for age-related dysfunction, exercise is currently the only intervention that has shown a remarkable efficacy for reducing the incidence of age-related disease171,172, improving the quality of life173 and even increasing mean and maximum lifespan in humans174,175. Its benefits can be seen even with modest implementation173. Although the key molecular players that mediate the protective effects of exercise against age-related disease are unknown, efforts are underway to identify the molecular players and whether we can harness such knowledge to improve the health of the ageing population.

Nutrition and ageing

Diet is probably one of the most important influences on health and ageing. However, it is an enormously complicated topic and beyond the scope of this Review (extensive discussion on this topic has previously been published176). The field of ageing has focused almost exclusively on the lifespan and healthspan effects of dietary restriction but, at the other end of the spectrum, overeating and the accompanying obesity shortens lifespan and decreases healthspan. In between these two extremes, there is strong evidence that optimal eating is associated with increased life expectancy and a reduction in the risk of all types of chronic disease. Many claims have been made for the competitive merits of different diets relative to one another. However, it is very difficult to conduct rigorous, long-term studies that compare different diets for their lifespan and healthspan effects using methodology that is devoid of bias and confounding variables. Without such direct comparisons, no specific diet can claim superiority over any others. However, a number of themes have emerged from studies that compare different diets and from the study of populations that are geographically associated with increased longevity (so-called ‘blue zones’). Diets that favour longevity and healthspan are generally characterized by minimally processed foods, being predominantly plant-based, low alcohol consumption and a lack of overeating.

Exciting recent developments are emerging in the nutrition field, such as intermittent fasting177, diets that mimic fasting178 and time-restricted feeding179. Recently, interest has grown in a ketogenic diet that is characterized by the endogenous production of high levels of the ketone body β-hydroxybutyrate. This diet has long been used as a treatment for childhood epilepsy and was recently shown to increase healthspan in two separate studies in mice180,181,182. The studies are supported by recent findings that β-hydroxybutyrate modulates the enzymatic activity of the epigenetic regulators, histone deacetylases, and thereby activates the expression of FOXO3183. Future research will focus on the healthspan and possible lifespan of these dietary interventions and the identification of their interactions with pathways that regulate ageing.

The need for biomarkers of ageing

The field of geroscience needs biomarkers to assess the ageing process and the efficacy of interventions to bypass the need for large-scale longitudinal studies. Medicine has undergone a progressive transformation during the past 40 years, changing from ‘sick care’—that is, care primarily focused on treating diseases after they occurred—to ‘healthcare’, in which unique risk factors for disease development are recognized and suppressed before disease onset. For example, neither high plasma cholesterol nor high blood pressure is a disease by itself but both are important risk factors for the development of myocardial infarction and strokes.

Similarly, ageing is not a disease but a notably strong risk factor for multiple diseases that include myocardial infarction, stroke, some ageing-associated cancers, macular degeneration, osteoarthritis, neurodegeneration and many other diseases. For example, cardiovascular risk doubles every 10 years past the age of 40, even after adjustment for other risk factors—the rough equivalent of adding a major new risk factor (smoking, hypertension and so on) every decade184. Decades of cardiovascular studies identified risk factors and showed that treating risk factors even when patients are asymptomatic prevented harm. Treatment guided by these cardiovascular biomarkers now extends earlier and earlier in life. The availability of true biomarkers of ageing, and associated clinical health outcomes and malleability to interventions162, would allow geroprotectors to be tested on an accelerated time scale. They would further allow for early identification of patients at high age-related risk throughout life and in various clinical contexts to target geroprotective treatments.

Early efforts to identify such markers have been unsuccessful, but recent developments using newer technologies such as high-throughput proteomics, transcriptomics and epigenomics indicate that such biomarkers do exist and could be of high clinical importance185. One possible biomarker, the epigenetic clock, is based on the measurement of DNA methylation at multiple sites and appears to correlate with biological age and age-related risk more than chronological age186,187,188. Advanced glycation end products represent another potential biomarker that accumulates with age and in several age-related diseases189. Furthermore, increased levels of some advanced glycation end products are also associated with increased mortality in humans190. There already is evidence that ageing biomarkers can be modified by interventions that target ageing, such as in the CALERIE study of calorie restriction in humans191. The identification of further biomarkers that predict biological age and disease risk will represent a huge stride forward in the efforts to combat age-related disease and dysfunction in humans.

We are now entering an exciting era for research on ageing. This era holds unprecedented promise for increasing human healthspan: preventing, delaying or—in some cases—reversing many of the pathologies of ageing based on new scientific discoveries. Whether this era promises to increase the maximum life span of humans remains an open question192. What is clear is that, 30 years after the fundamental discoveries that link unique genes to ageing, a solid foundation has been built and clinical trials that directly target the ageing process are being initiated. Although considerable difficulties can be expected as we translate this research to humans, the potential rewards in terms of healthy ageing far outweigh the risks.