Should I pay out-of-pocket to have my telomeres measured? My telomeres are shorter than average, what does that mean? Are there treatments to lengthen my telomeres? These questions from patients will become increasingly common with the growing access to commercial putative aging biomarker products. Although offering these products directly to consumers is surely premature, the basic and translational science that inspires these products is a serious and exciting endeavor with immense potential.1,2 Chronological aging is a major risk factor for most chronic diseases, multimorbidity, and geriatric syndromes, and progresses at the same rate for everyone. Conversely, biological aging, the mechanism by which chronological age affects risk of age-related conditions, changes at different rates based on individual genetics, environmental and early life exposures, and health-related behaviors. Clinicians already use clinical surrogates of biological age, including physical and cognitive function, functional status, and frailty, which increase with age at the population level but vary widely within individuals of the same chronological age. Advances in basic science have led to the identification of multiple biological mechanisms or “hallmarks” of aging, including genomic instability, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, and telomere attrition or shortening.3 The Geroscience Hypothesis posits that modulating these biological mechanisms of aging will delay, prevent, or treat multiple age-related diseases and conditions simultaneously, prolonging the healthy years of life.1 As part of the effort to test this hypothesis in humans, the development of measures of biological aging (“geroscience-guided biomarkers”) has become an explicit goal of aging researchers and geroscience experts.2,4 They argue that geroscience-guided biomarkers could inform our understanding of pathophysiologic mechanisms of aging in disease, act as surrogate end points in interventional clinical trials, guide therapies targeting these mechanisms, and strengthen individual age-related risk prediction models. As a growing chorus of thought leaders advocate that both aging researchers2 and clinicians who treat older patients1 embrace geroscience, those new to the field may not be aware of the multiple potential uses of geroscience-guided biomarkers.
In this issue of JAMA Internal Medicine, Schneider et al(REF) report that mean leukocyte telomere length (LTL), a geroscience-guided biomarker candidate, is associated with overall and disease-specific mortality in a large prospective cohort study. Mean LTL was measured at a single baseline visit for >470,000 UK BioBank participants, enrolled at a median of age 56 years (range 37-73) and followed for a mean of 12 years. The authors find that shorter mean LTL is associated with a small but statistically significant increased risk of all-cause mortality, particularly for respiratory disease, liver disease, and hematopoietic cancers, as well as COVID-19. The associations are independent of sex, body mass index, ethnicity, health-related behaviors, and, importantly, chronological age. Mean LTL was not associated with risk of death from neurological and endocrine diseases, or other cancers. This study is notable for several reasons. First, the findings support the premise, based on the Geroscience Hypothesis, that a single biomarker based on a biological mechanism of aging could be associated with numerous causes of death, particularly from age-related conditions. Second, an association between mean LTL and all-cause mortality has been inconsistently observed in prior studies; indeed, the ability of mean LTL to predict death has been appropriately questioned.5 Lastly, observed associations between mean LTL and death due to pulmonary diseases is supported by the mechanistic link between telomere gene mutations and idiopathic pulmonary fibrosis.6 To help readers interpret and contextualize these results, we will describe our approach to evaluating the geroscience-guided biomarker literature based on both research and clinical uses.
Geroscience-guided biomarkers may help researchers determine the contribution of biological aging to age-related conditions.
Schneider et al(REF) suggest that systemic telomere shortening is associated with slightly lower overall survival and could be an important biological mechanism of several age-related respiratory diseases (including COVID-19), liver diseases, and hematopoietic cancers. These findings could rest on the explanation that accelerated biological aging via particular pathways plays an outsized role in specific age-related conditions. Alternatively, all biological aging pathways may lead to the same common dysfunctional state of low reserve and resilience and increased susceptibility to age-related disease and functional impairment. A key unanswered question is which biological mechanisms of aging cause which age-related conditions. Of course, we cannot ethically edit genes or implement a human adaptation of the NIA-funded Interventions Testing Program, which is evaluating hundreds of compounds in mice to determine whether they prevent age-related disease and extend lifespan. Accordingly, large-scale epidemiologic studies with concurrent measures of physical and cognitive function, functional status, age-related chronic diseases, and multiple geroscience-guided biomarkers measured serially will be required to validate the Geroscience Hypothesis.
In building this evidence base, geroscience-guided biomarkers that lie on the causal pathway from chronological aging to age-related pathophysiology and disease will be uniquely useful. However, biomarkers that are surrogates of biological mechanisms of aging and are easier (e.g., blood-based vs tissue biopsy or in vivo monitoring) or less expensive to measure are still valuable. Multiple biomarkers representing different mechanistic pathways could potentially be combined to generate a composite measure of biological age or a standard set of geroscience-guided biomarkers to map the posited contribution of biological aging to age-related conditions. This hypothesis, too, will need to be rigorously tested before these biomarkers can replace the relatively straightforward and validated, self-reported functional measures that integrate the multidimensional aspects of biological as well as social, behavioral, and psychosocial changes of older age. Eventually, a subset of validated geroscience-guided biomarkers, likely in conjunction with phenotypic and functional measures, may be used to identify individuals who will derive the greatest benefit from interventions targeting biological mechanisms of aging.
Geroscience-guided biomarkers may offer greater efficiency in testing interventions that modulate biological mechanisms of aging in humans.
Testing geroscience interventions in randomized, placebo-controlled clinical trials aimed at prolonging lifespan is critical to bridging the translational gap from animals to humans. Primary outcomes would likely be new onset age-related disease, multimorbidity, functional decline, or death. However, geroscience-guided biomarkers could provide mechanistic insights and confirm that the interventions change the rate of biological aging as intended. A validated geroscience-guided biomarker that meets the strict standard for a surrogate end point could decrease the size, duration, and cost of future trials. Justice and colleagues have thoughtfully outlined criteria for the use of blood-based biomarkers in such trials: 1) adequate measurement reliability and feasibility, 2) relevance to aging (and aging biology), 3) robust and consistent ability to predict all-cause mortality, clinical and functional outcomes, and 4) responsiveness to intervention.4 In the case of mean LTL, Schneider et al(REF) have provided data from the largest study to date on the association between mean LTL and mortality, although the association is far too small for this biomarker to serve as a surrogate end point and several Justice et al. criteria have either not been met or tested.
Geroscience-guided biomarkers may inform individualized prediction models.
Although chronological age is a powerful predictor of myriad health outcomes, it is a terribly imprecise prognostic biomarker. Frailty and functional assessments are often used as clinical surrogates of older biological age to complement chronological age. Geroscience-guided biomarkers may greatly improve precision in predicting health events that influence clinical decision making and provide clinicians with more accurate prognostic information. To move this use-case forward, mean LTL and additional candidates will need to be tested alongside clinical surrogates of biological aging to determine whether they improve risk prediction in applications ranging from cancer screening decisions to perioperative risk assessment.
Accordingly, in answer to our curious patients, we recommend against mean LTL measurement and share our view that despite interesting mechanistic insights there is yet insufficient evidence to support the clinical use of this biomarker. We use the opportunity to explain the Geroscience Hypothesis and what is already known about the health and lifespan prolonging benefits of regular exercise, healthy eating, smoking cessation, maintaining a healthy weight and cardiovascular risk profile, cognitive stimulation, and social engagement. There is much to be enthusiastic about looking to the future of geroscience-guided biomarkers. We are confident that they will have a significant role in helping to elucidate novel geroscience interventions to prolong the healthy years of life.
REFERENCES
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