https://orcid.org/0000-0002-5697-2189
Abstract
Geroscience posits that molecular drivers underlie the aging process. Gerotherapeutics entail strategies to counter molecular drivers of aging to reduce the chronic diseases and geriatric syndromes they trigger. Although the concept of gerotherapeutics for prevention has generated much excitement, the implications of prescribing potentially harmful medications to older adults who are “healthy” have been associated with many delays. Concerns regarding safety and valid endpoints have contributed to holdups. In contrast, it has been relatively easier to implement trials of medications with gerotherapeutic properties as novel approaches to remedy disease. In these applications, the risks of the medications are easier to justify when therapeutic benefits are perceived as outweighing the harms of the disease. Likewise, metrics of effective disease treatments are often seen as more reliable and quantifiable than metrics of health prolongation. Overall, clarifying geroscience mechanisms in disease therapeutic applications provides key opportunities to advance translational geroscience, especially as preventive geroscience trials are often encumbered. In this review, gerotherapeutic benefits of canakinumab, cholchicine, and zoledronic acid as parts of disease management are considered. Longevity Clinics and other opportunities to advance translational geroscience as parts of contemporary care are also discussed.
Geroscience is premised on principle that molecular key drivers underlie the aging process. Gerotherapeutics aims to counter age-related molecular damage. Hypothetically, if key drivers of aging are slowed or eliminated, the portion of one’s life free of chronic diseases, geriatric syndromes, disability, and other age-related vulnerabilities can be extended. Such a healthful phase of lifespan is now termed as “healthspan.” The premise of healthspan stands out as an enticing health ideal for the growing population of older adults. Still, the conception of administering gerotherapeutic medications that may be harmful to adults who are “healthy” at baseline is in contradistinction to long-established principles wherein risks of treatment are justified by the greater risks of the disease they are intended to remedy. Furthermore, it is relatively easier to characterize the benefits of a medication in relation to the harms of a disease as compared to the more ambiguous precept of extending healthspan. Thus, in spite of the strong conceptual appeals of gerotherapeutics to extend healthspan, translational geroscience research often remains delayed by concerns regarding excessive risk and unreliable endpoints.
Nevertheless, there are also geroscience principles inherent in many disease-based therapeutics. Related trials have often been able to move forward without the same extent of encumbrances that commonly delay geroscience prevention initiatives.
In this report, we describe some of the barriers to slowing Targeting Aging by Metformin (TAME), a gerotherapeutic prevention trial with metformin, and the relative efficiencies of gerotherapeutic translational research oriented to disease management. Pertinent studies with canakinumab, cholchicine, and zoledronic acid are reviewed. Longevity Clinics and other opportunities to advance translational geroscience as parts of contemporary care are similarly considered.
Telltale Implications of TAME
The delayed launch of the long-anticipated trial, TAME (1) to study the effectiveness of metformin to slow or circumvent incident cardiovascular disease, cancer, and cognitive impairment demonstrates some of the inherent problems of implementing prevention translational geroscience trials. Beyond the well-established efficacy and safety of metformin to improve glucose metabolism for adults with diabetes, epidemiological studies have suggested it may also circumvent age-related disease. TAME is a translational geroscience clinical trial that intends to test this ground-breaking concept.
From the time TAME trial was conceptualized a decade ago, it generated much hype and excitement. Remarkably, even after 10 years of anticipation and planning, it remains unstarted (2). In 2015, the American Federation of Aging Research offered about $9 million toward a projected budget of 30–50 million dollars for a sufficiently powered trial. Many thought that the balance would be easily funded. But despite significant efforts of its investigators, delays have persisted.
Even though TAME does not require Food and Drug Administration (FDA) approval to study an already approved medication (for diabetes, polycystic ovarian syndrome, and other indications), significant efforts have been made by the investigators to clarify parameters the FDA will require to expand the indications for metformin if the trial is positive. To do this, the investigators struggled to determine endpoints the FDA deemed suitable. Rather than following a traditional FDA format of single disease-therapeutic targets, TAME focuses on a composite primary endpoint that links stroke, heart failure, dementia, myocardial infarction, cancer, and death. Likewise, rather than focusing on the disease itself, TAME focuses on delaying the onset of disease, that is, extending the years in which participants remain in good health.
The TAME investigators also assert that while they are not required to get Investigational New Drug (IND) authorization from the FDA, they are still planning to obtain one as full funding is secured.
Although some assert that even if TAME is never completed, the widespread interest it generated has successfully advanced the premise of gerotherapeutics for healthspan. Nonetheless, TAME also lays bare some of the difficult challenges associated with the implementation of geroscience-based prevention trials.
Geroscience and Cardiovascular Care
In contrast to geroscience applications to augment healthspan, the application geroscience principles to treat diseases has been relatively more efficient. Gerotherapeutics targeting inflammation stand out as a key example wherein gerotherapeutics have been successfully applied as novel cardiovascular disease (CVD) therapy.
Whereas geroscience focuses on multiple hallmarks of aging as drivers of downstream disease. Inflammaging is a common outcome, even when different aging hallmarks are triggered (3). This is consistent with the “Unitary Theory of Fundamental Aging Mechanisms,” which highlights the interdependence between the mechanisms of aging, wherein one aging hallmark can affect others (4). Inflammation may be conceptualized as a collective biomarker of the failure of biological resilience against damage accumulation with aging (5). IL-6, C-Reactive protein (CRP), and other inflammatory mediators tend to increase with age (6).
In parallel with evolving insights in geroscience, pioneering experts in cardiovascular medicine reported that inflammaging was a significant factor in the progression of CVD. Inflammaging was demonstrated to provoke multiple CVDs, including coronary heart disease, cerebrovascular disease, peripheral arterial disease, myocardiopathy, valvular dysfunction, and heart failure. In what was then a groundbreaking approach to CVD, anti-inflammatory therapy with a monoclonal antibody canakinumab was studied in a population at high risk for CVD and CVD mortality.
The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) studied >10 000 adults with previous myocardial infarction and a high-sensitivity CRP level of 2 mg or more per liter. It proved that neutralizing IL-1β with canakinumab for over a median of 3.7 years interrupted a causal pathway in recurrent CVD events, especially in participants who showed a greater than median decline in the inflammatory markers CRP and IL-6 (7). Participants receiving canakinumab had a significantly lower rate of recurrent cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) than placebo (hazard ratio vs placebo, 0.83; 95% CI: 0.73 to 0.95; p = .005), independent of lipid-level lowering.
The CANTOS is remarkable as a novel approach to CVD prevention, but it stands out even more as it showcases key translational geroscience benefits that extend beyond CVD. The same medication that reduced CVD also reduced incident lung cancer and lung cancer mortality (8), anemia (9), gout (10), hospitalizations for HF (11), and even replacements of the hip or knee in the same study population (12). Furthermore, even though there were known infection risks associated with anti-inflammatory therapy, that did not dissuade the investigators from studying this anti-inflammatory medication, as the goal to alleviate CVD was the dominating consideration, and the benefits were felt to justify the risks. Indeed, neutropenia was more common among those receiving canakinumab, with significantly more deaths attributed to infection or (incidence rate, 0.31 vs 0.18 events per 100 person-years; p = .02), but that did not detract from the trial’s reputed success.
Notably, since CANTOS, additional trials have explored anti-inflammatory therapeutics for CVD. Among patients with a recent MI, colchicine at a dose of 0.5 mg daily significantly lowered the risk of ischemic cardiovascular events (hazard ratio, 0.77; 95% CI: 0.61 to 0.96; p = .02) (13). Similar benefits of colchicine have been demonstrated for other CVDs as well (14). Notably, mechanisms underlying colchicine’s anti-inflammatory effects are very different than canakinumab and entail its direct interaction and transcriptional changes on tubulin microtubules of the inflammasome, resulting in conformational changes and destabilization (15). Colchicine has yet to be reported as an effective therapy for other age-related risks rooted in inflammation, such as other chronic diseases and frailty, but its utility for broader geroscience associations seems an important opportunity to explore.
Anti-osteoporosis Therapy
Zoledronic acid is a routinely used bisphosphonate for the treatment of osteoporosis, Paget’s disease of bone, and skeletal complications of cancers, such as hypercalcemia of malignancy or skeletal metastases. Zoledronic acid has a long history of clinical use with a well-established benefit-to-risk profile (16). Based on strong clinical evidence, the efficacy of zoledronic acid induces a reduction of bone turnover, improvement in bone mineral density (BMD), and substantial fracture risk reduction (17). Unexpectedly, treatment of zoledronic acid treatment has been associated with the extension of lifespan (ie, reduced mortality) (18,19), as well as lower risks for cancer (20,21), and cardiovascular disease (20,22,23). Benefit to overall mortality has recently been questioned in a meta-analysis of 6 clinical trials; however, the authors call out uncertainty in their findings relating to significant heterogeneity of the results (24). Nevertheless, given the healthspan benefits outlined previously, zoledronic acid can be leveraged across several age-onset conditions.
Mechanistic studies in preclinical models have also shown that zoledronic acid extends lifespan in a mouse model of Hutchinson–Gilford progeria syndrome (25), inhibits neoplastic growth and distant extension (26,27), protects against radiation effects (28), and maintains or improves postchemotherapy and normal muscle function (29–31). Recent evidence now suggests that zoledronic acid can modulate cellular senescence by normalizing the circulating senescence-associated secretory phenotype and reducing markers of cellular senescence such as p16 and p21 (31).
Taken together, the weight of evidence implicates zoledronic acid as a translational geroscience-based agent to be considered in the clinic for multimorbidity when there is already an indication for a single-disease state such as osteoporosis.
Translational Geroscience to Overcome Healthcare Disparities and Underrepresentation of Older Adults in Clinical Trials
Geroscience is often touted for its conceptual potential to overcome the health care disparities that tend to be entrenched in adults with lower socioeconomic status, poor access to health care, and/or from marginalized communities. However, multiple procedural, ethical, and philosophical concerns (32–36) undercut this ideal. Among these issues are the ambiguous alignment of translational geroscience with health disparities (especially those associated with socioeconomic status; ie, longevity therapeutics for those that can afford them), the related high and usually uninsured costs associated with gerotherapeutics and the still daunting gap between preclinical models and clinical translation.
Older adults are commonly excluded from clinical trials (37,38), and in the case of testing gerotherapeutics, this would limit the advancement of understanding their potential in the very population that could best evaluate their efficacy. Older adults, especially those with multimorbidity and polypharmacy, are grossly underrepresented in clinical trials, making it very difficult to generalize study results to the older population at large (38), and represents a missed opportunity to test an important aspect of the geroscience hypothesis; namely, that aging is fundamentally responsible for chronic diseases that compose the multimorbidity phenotype. Obstacles that contribute to this poor representation include challenges for the inclusion of older adults in clinical trials (eg, persistence in exclusive single disease-based focus of trials, complex disease states, atypical presentations, impairments to optimal health-related communications) (35,38–40). Other issues include the ethical conduct of research in older (vulnerable) populations and their participation in first-in-human clinical trials on translational geroscience-based interventions (36). The limitation of underrepresentation of older adults in clinical trials is extended in trials on gerotherapeutics to those older adults with complexities of health status as well as inadequate outcome measures that take into account physical and cognitive functioning that cut across chronic disease states shared by these individuals.
Recruitment of older subjects has been facilitated by NIH policy mandating the inclusion of older adults (41–43). The Federal Drug Administration also has issued industry guidance for industry on the inclusion of older adults in cancer clinical trials (44). Frameworks for the successful inclusion of older adults in research have been proposed that address many of the above challenges (45–47). To date, however, information from major geroscience trials remains relatively limited (48,49) so how do we safely translate existing geroscience-based evidence into the clinic?
The Evolving Story of Longevity Therapeutics
So-called Longevity Clinics, aimed at delaying the aging process, offer a wide gamut of services ranging from illness-specific treatments to those that purportedly counter natural aging itself. The provocative name alone conjures promises that seem undeliverable with the paucity of current evidence-based interventions vigorously trialed in humans to measure life extension benefits. Other variables associated with these clinics include cost (mostly not covered by health insurance), use of prognostic biomarkers not yet standard of care, screening for diseases irrespective of estimated life expectancy, whole body imaging, and other medical testing without clear indication for purpose. Longevity clinics may be viewed as a potential threat to successful clinical trials on translational geroscience given that provided services are not always evidence-based and currently, there is no formal regulatory oversight or guidance.
Fueled by desires for longer life and personalized medical management, many of these clinics cater to those with sufficient affluence to afford noninsurable care, who are also willing to take on the risks of hyped diagnostics and interventions. At their best, longevity clinics encourage clients to live healthy lifestyles, sustain healthy behaviors, pursue age-appropriate disease screening, and utilize medications and interventions indicated for specific disease states with the goal of optimizing healthspan benefits based on disease-oriented clinical evidence. At their worst, longevity clinics over-diagnose benign problems, endorse unnecessary procedures, expose clients to unapproved or unproven therapies, and may also worsen age-related health disparities. Although longevity medicine is slowly being pursued on scientific grounds (50–53) evidence-based guidelines are thus far lacking.
Paradigm for Current Use of Geroscience Interventions in Disease Treatment and for Healthspan Benefits
We propose a pragmatic approach to introducing translational geroscience into the clinic (Figure 1). This paradigm, based on incremental knowledge progression of aging-related clinical research, incorporates both non-pharmacological and pharmacological strategies and risk/benefit analyses commonly used in exercise, dietary, and medication prescriptions for single-disease states, where the added healthspan and multimorbidity benefits are value-added. In the 2 examples provided here, among the therapeutic choices for CVD and osteoporosis, canakinumab and zoledronate, respectively, both target single-disease states and also have strong, evidence-based support for pleotropic benefits that address healthspan, multimorbidity, and even lifespan. As with any therapeutic interventions, the risk/benefit considerations apply, even for exercise (eg, transient increase in arrhythmia with vigorous activity) and dietary restriction (eg, loss of BMD and lean body mass) (54–56). With these basic principles in mind, however, it is possible to practically and safely move forward toward the application of translational geroscience into the clinics.
Pragmatic approach for introduction of translational geroscience into the clinic.
Funding
D.E.F. receives funding support from National Institutes of Aging R01AG058883, R01AG060499, U19AG065188, R01AG073633, R01AG077179, and P30AG024827; VA RR&D 1I21RX004409 and HSR&D1 I01 HX003518; and PCORI IHS-2021C3-24147. R.J.P. funding support from National Institutes of Health P01AG62413, R01 AG72301, R01AG83464, R01AG82681, R01HL12667, R25AG073119, and ULTR02377; additional support is from GlaxoSmithKline, Incyte, Ipsen, and Genome Protection.
Conflict of Interest
D.E.F. and R.J.P. have no conflicts of interest.
