Introduction: the geroscience hypothesis
Aging involves a complex array of well-defined categories of biological processes that represents a key driver contributing to the exponential increase in the risk of many diseases and death 1. The US government publishes an annual report of the age-stratified rates of major disease-specific death rates, including deaths from heart disease, cancer, stroke, type 2 diabetes, and Alzheimer’s disease 2. Strikingly, the most common and by far the most potent risk factor of all is chronological age itself. This is not unique to the USA. Evidences from the multinational Global Burden of Disease project and other international epidemiologic research indicate that old age is the leading risk factor for chronic disease, disability, and death, internationally 3. These observations suggest that there is a fundamental biologic basis underlying aging that increases risk collectively. If aging is the common and the major risk factor for these chronic diseases, then unless aging itself is therapeutically targeted, efforts focused on preventing individual diseases will have limited net impact on a population basis because one disease will be exchanged for another 4. Interventions that slow the progression of aging per se, could delay the onset of age-related diseases and death collectively, rather than one at a time 5–7 (Fig. 1). This is the premise underlying the geroscience hypothesis: by targeting aging we can prevent or delay multiple chronic diseases and death simultaneously.
The geroscience hypothesis is supported by recent, remarkable progress in understanding the basic biology of aging as well as identifying interventions that can extend healthy lifespan. Geroscience research has advanced unifying mechanisms and theories to explain the broad biologic aging process and to identify pathways that can be targeted to delay or reverse age-related decline 8–10. Lifespan has been verifiably modulated by genetic (such as the insulin/insulin-like growth factor-1 signaling pathway) and dietary (such as caloric restriction) interventions in multiple model systems, independent of disease modifiers across diverse and evolutionarily distant species 11,12. Biologic aging can also be targeted pharmacologically, and several promising candidates have been identified by National Institutes of Health/National Institute on Aging sponsored Interventions Testing Program, a multicenter preclinical program to test diets, drugs, and other interventions effects on disease prevention and lifespan extension in genetically heterogeneous (outbred) mice 13,14. Of the diets and drugs tested, the Interventions Testing Program showed lifespan extension with nor-dihydroguaiaretic acid, aspirin, acarbose, 17-α-estradiol and, most notably, the mTOR inhibitor rapamycin 15,16. In addition, a new class of drugs, termed senolytics was recently discovered 17. Senolytics selectively kill senescent cells 17,18. Late-life intervention with senolytics in mice delays age-related functional decline and extends median lifespan 19. Likewise, there is a growing body of evidence that metformin can delay aging. Though lifespan effects are relatively modest (∼4–6% extension of median lifespan across mouse breeds), the effects on health are substantial, with improvements on tests of physical and cognitive function, cataracts, oral glucose, and insulin tolerance improved by up to 30% 20,21. These preclinical studies provide a proof-of-concept that therapeutically targeting fundamental mechanisms of aging can improve healthspan and lifespan. The challenge comes in translation, as large-scale clinical trials designed to target aging have never before been attempted.
Geroscience-guided clinical trials
A Geroscience Network of basic aging biologists, gerontologists, geriatricians, and clinical trial experts was initiated during several interprofessional meetings (NIH R24 supported Geroscience Network, J. Kirkland, N. Barzilai, S. Austad; planning co-funded by American Federation of Aging Research) 22,23. Consensus emerged that a large-scale clinical trial on aging was needed to test the hypothesis that the biology of aging can be modulated to reduce multiple age-related health conditions simultaneously. A trial of this kind would (i) provide immediate clinical application with potential to extend healthy lifespan and reduce healthcare costs, (ii) serve as a template for future efforts and drug development, (iii) increase scientific knowledge and facilitate discovery of biomarkers, and (iv) establish a defined and rigorous standard of proof against which the ‘anti-aging’ claims of nutraceutical or pharmaceutical companies could be judged. Metformin was identified as an attractive tool to target aging and age-related multimorbidity in a clinical trial, because it: (i) targets molecular and cellular drivers of aging that may exert positive effects on lifespan and healthspan, (ii) is a generic and relatively inexpensive medication, (iii) has an excellent safety record, and (iv) can be generally well tolerated with long-term use in a large population of aging adults 22. Finally, given metformin’s use in clinical research and practice, effects could be estimated from randomized clinical trials and observational studies in humans, as reviewed previously 6.
A aim of the Geroscience Network is to identify trial designs that would facilitate regulatory approval for the use of a drug for the purpose of delaying age-related comorbidity and enhancing healthpsan. Discussions were initiated with the Food and Drug Administration (FDA) to harmonize research and drug approval objectives. FDA and regulatory officials emphasized the importance of an outcome on the basis of disease, rather than markers of function or syndromes. In this manner, the FDA served an informative role in the selection of a primary outcome for a proposed clinical trial on aging: to test whether random assignment to metformin versus placebo reduces the incidence of new age-related chronic disease [myocardial infarction, stroke, hospitalized heart failure, cancer, dementia, or mild cognitive impairment (MCI)] or death. Through this deliberate process of scientific and regulatory engagement the study ‘Targeting Aging with Metformin’ (TAME) was devised as the first geroscience-guided aging outcomes trial, with current efforts focused on actualization.
The TAME trial: a case study
TAME was conceived as a 6-year double-blind placebo-controlled multicenter clinical trial designed to determine whether metformin (1500 mg/day) prevents the accumulation of multiple age-related disease and other aging phenotypes, rather than any individual disease. As originally designed, it would enroll an ethnically diverse population of ~3000 men and women aged 65–80 years, without diabetes, but at a high risk for major age-related diseases and mortality at multiple clinical sites in the USA. In addition to age, 4-m gait speed 0.4–1.0 m/s or prevalent cardiovascular disease, cancer, or MCI are proposed inclusion criteria to provide straightforward screening and entry of a generalizable population, and allow entry by persons with evidence of accelerated aging. To determine whether metformin targets multiple-aging pathways rather than having an effect focused on a specific disease or mechanistic pathway, TAME was designed to capture major components of aging grouped into three main outcome areas: (i) clinical outcome: new age-related chronic disease (myocardial infarction, stroke, hospitalized heart failure, cancer, dementia or MCI) or death; (ii) functional outcome: major age-related functional outcomes (major decline in mobility or cognitive function, or onset of severe activities of daily living limitation); (iii) biological outcome: biomarkers of aging comprise an exploratory trial outcome intended to strengthen the biological underpinnings guiding the TAME trial.
TAME’s primary clinical outcome was comprised of diseases expected to directly impact healthcare use, and represent diverse clusters of families of diseases, such that intervention effects can be broadly ascribed to aging, rather than a narrow set of mechanistic pathways driving a single disease. In addition, a plurality of effect was expected: TAME was not designed to have sufficient power to show a significant effect on any one disease. On the basis of recommendations from the steering committee and regulatory advisors, incidence type 2 diabetes mellitus (T2DM) was removed from the primary clinical disease outcome as metformin is an antidiabetic drug that has been previously shown to reduce the risk of T2DM, and even prevented T2DM in the Diabetes Prevention Program after its use has been stopped for months 24,25. TAME’s secondary outcome was designed to capture changes in functions that are important for the preservation of independence as we age including declines in cognition and mobility, and new limitation in activity of daily living. The burden of comorbidity is associated with functional decline, but does not explain a substantial proportion of functional changes. This suggests that some part of the functional decline is attributable to aging per se, which is supported by animal models and emerging evidence from clinical trials 20,26.
Aging biomarkers and molecular endpoints for clinical trials
Recently, consensus groups have identified overlapping sets of 7–9 largely interdependent cellular and molecular mechanisms that underlie aging (‘pillars of aging’ or ‘hallmarks of aging’), including epigenetic alterations, deregulated nutrient sensing, loss of proteostasis, inflammation and altered intracellular communication, and cellular senescence 10,27. Nevertheless, translation of these processes to in-vivo surrogate measures in humans has not yet been accomplished, and most existing markers are not sufficiently developed for use in clinical trials 28,29. Substantial research activity from the biology of aging is underway to develop markers and multiassay indices to characterize biological aging 30,31, but currently there is no aging biomarker consensus or hierarchical structuring to support TAME’s trial outcomes.
Nonetheless, biomarkers provide a necessary strategy for evaluating interventions and provide evidence that the biology of aging is targeted. Given the trial context of TAME, biochemical markers that can be easily measured in blood samples collected across clinical sites in all 3000 participants at multiple trial timepoints was necessary. To select a set of blood-based biomarkers a TAME Biomarkers Workgroup was convened and a rigorous evidence-based selection processes carried out. The workgroup derived criteria for selection; emphasizing: (i) measurement reliability and feasibility; (ii) relevance to aging; (iii) robust and consistent ability to predict all-cause mortality, clinical, and functional outcomes; and (iv) responsiveness to intervention. Application of these selection criteria to the current literature reveals a paucity of blood-based biomarkers with adequate foundational evidence for large-scale clinical trials on aging. A short list of prominent markers did pass selection criteria on the basis of expert opinion and available evidence, including markers of inflammation (interleukin-6, tumor necrosis factor-α receptor, C-reactive protein), stress response/mitochondrial health (GDF15), nutrient sensing (insulin, insulin-like growth factor-1), and three markers of metabolic, cardiovascular, and kidney health (hemoglobin A1c, NT-proBNP, and cystatin-C) 32. A panel of a priori-defined biomarkers has inherent utility, but may not capture the complex and multifactorial processes underlying aging. This gap can be addressed by high-throughput ‘omics’ technologies, including genome-wide methylation patterns, transcriptomics, proteomics, and metabolomics. Investigations examining the interconnected pathways and molecular networks will offer holistic approaches to enhancing TAME and integrating its trial outcomes with mechanistic and molecular discovery. The aim of these multiomic approaches will be to uncover new molecular signatures and targets for future geroscience-guided therapeutics.
On the basis of TAME development, a biomarker strategy that combines evidence-based blood-based biochemical measures with data-intensive technologies and specimen biobanking is desirable for clinical trials on aging. A concise set of well-justified blood-based biomarkers to measure in all study participants is realistic for a multisite clinical trial, but providing opportunity for high-throughput platforms to comprehensively analyze genes, transcripts, proteins, and other significant molecules is of paramount importance. Central to this endeavor is the proposed cultivation of an extensive and rigorously collected biorepository, and dedicated efforts to scientific engagement to provide a resource for emerging science and future innovation.
Geroscience could fundamentally revolutionize the traditional approach of developing drugs to treat or prevent one disease at a time by targeting disease-specific pathways to an approach that targets the aging process, and in this manner will influence many age-related diseases and functional outcomes collectively. A clinical trial on aging is being designed as a prototype for future efforts to test promising agents identified by basic biology of aging and geroscience research. If such a trial is successful, the impact will be three-fold: (i) direct and immediate impact with respect to the prevention of multiple age-related chronic diseases in persons at high risk; (ii) proof-of-concept that by targeting aging itself, healthspan and lifespan can both be increased, which in the future could potentially lead to a new FDA indication for drugs to prevent age-related diseases; and (iii) stimulation of drug discovery, with the potential of developing new and better compounds to extend healthy lifespan.
American Federation for Aging Research (AFAR); the Glenn Center for the Biology of Human Aging (Paul Glenn Foundation for Medical Research); National Institutes of Health: K01 AG059837-01 (J.N.J.), P30 AG021332 (S.K.B., J.N.J.); AG048023, AG052608, GM124922 (G.A.K.); P30 AG038072 (N.B.), P01 AG043376 (L.J.N., P.D.R.), U19 AG056278 (L.J.N., P.D.R., N.B.).
Conflicts of interest
There are no conflicts of interest.
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