Evolution of Natural Lifespan Variation and Molecular Strategies of Extended Lifespan

Abstract To understand the genetic basis and the selective forces acting on longevity, it is useful to employ ecologically diverse individuals of the same species, widely different in lifespan. This way, we may capture the experiment of Nature that modifies the genotype arriving at different lifespans. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered wide diversity of lifespan. We sequenced the genomes of these organisms and analyzed how their replicative lifespan is shaped by nutrients and transcriptional and metabolite patterns. By identifying genes, proteins and metabolites that correlate with longevity across these isolates, we found that long-lived strains elevate intermediary metabolites, differentially regulate genes involved in NAD metabolism and adjust control of epigenetic landscape through conserved, rare histone modifier. Our data further offer insights into the evolution and mechanisms by which caloric restriction regulates lifespan by modulating the availability of nutrients without decreasing fitness.


PRESIDENTIAL SYMPOSIUM: PHYSIOLOGICAL VS. MOLECULAR CLOCKS, STUDIES FROM MICE TO HUMANS Chair: Blanka Rogina
Aging is associated with a functional decline in metabolic, physiological, proliferative, and tissue homeostasis leading to deterioration at the organismal level, and an increased risk for disease and death. Genetic, pharmacological and nutritional interventions have been successfully used to preserve metabolic health, which leads to preserved healthspan and extended longevity. However, the rate at which animals in a population become impaired by age-related frailty and disease is highly variable and several aging clocks that measure different age-modulated processes in the organism are being use as potential markers of the rate of aging. These molecular clocks allow to a more accurate quantification of the biological age of animals. Nevertheless, there is still room for further discussion in terms of the strengths and weaknesses of these biomarkers, in order to probe their biological significance, cellular mechanisms, and epidemiological potential to further explore their long-term benefit of increasing healthspan. This symposium will discuss new approaches to delineate physiological versus molecular clocks based on studies in mice and humans. We will also discuss species-specific metabolic mechanisms based on longitudinal studies in mice, monkeys and humans. Development of reliable and valid measurements to quantify biological aging is a critical frontier geroscience. Originating in accumulations of molecular changes, biological aging undermines resilience within cellular networks and organ systems, driving disease, disability, and mortality. Measurements of biological aging have been proposed at several molecular and physiological levels of analysis. But agreement between measures implemented at different levels of analysis is low. The timing at which aging processes manifest at different levels of biological organization may vary, with the result that signs of aging manifest in one level of analysis are not yet observable in another. And different aging processes may be most apparent in different molecular levels of analysis. In midlife humans, aging-related changes are manifest at multiple molecular and physiological levels, making this population ideal for development of measurements that integrate information across levels of analysis to more precisely quantify the state and pace of biological aging.

AGING ACROSS THE LIFESPAN: RETHINKING THE DAVID BARKER HYPOTHESIS Luigi Ferrucci, National Institute on Aging, Baltimore, Maryland, United States
For many years, the scope of geriatric medicine has been the care of older persons affected by multiple disease with the aim of improving their functional status and optimize quality of life. As our knowledge of the mechanisms of aging grows rapidly, it is becoming clear that accomplishing this scope requires taking a life-course perspective. Research have failed to establish a clear-cut distinction between normal aging and pathology leading to the hypothesis that aging is at the root of chronic diseases, and difference in health can be ascribed to different aging rates. Research in model organisms, suggest that aging can be modified with consequent changes on healthspan and longevity. Interventions that modulate aging may ultimately prevent most-age-associated diseases and their consequences. From this perspective, geriatric medicine is the leading and most promising branch of biomedical science. Challenges remain: first, demonstrating that certain interventions slow down the aging rate requires the valid measure of aging, and while many tools were developed, "epigenetic clocks" being the most promising, the underline mechanism that drive their changes with aging and validity in clinical applications are unclear. We do not know whether variability in the rate of biological aging assessed in old age are already detectable in younger individuals and person-specific rates remain constant during life. In 1986, David Barker stated the hypothesis that the period of gestation, characterized by a strong epigenetic imprinting, affects health and wellbeing across life, perhaps by setting the aging rate. Perhaps pediatric and geriatric medicine are more connected than previously believed.

EVOLUTION OF NATURAL LIFESPAN VARIATION AND MOLECULAR STRATEGIES OF EXTENDED LIFESPAN Alaattin Kaya, Virginia Commonwealth University, Richmond, Virginia, United States
To understand the genetic basis and the selective forces acting on longevity, it is useful to employ ecologically diverse individuals of the same species, widely different in lifespan. This way, we may capture the experiment of Nature that modifies the genotype arriving at different lifespans. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered wide diversity of lifespan. We sequenced the genomes of these organisms and analyzed how their replicative lifespan is shaped by nutrients and transcriptional and metabolite patterns. By identifying genes, proteins and metabolites that correlate with longevity across these isolates, we found that long-lived strains elevate intermediary metabolites, differentially regulate genes involved in NAD metabolism and adjust control of epigenetic landscape through conserved, rare histone modifier. Our data further offer insights into the evolution and mechanisms by which caloric restriction regulates lifespan by modulating the availability of nutrients without decreasing fitness.

FRAILTY IN PRECLINICAL MODELS: IMPACT OF HEALTHSPAN ON DISEASE EXPRESSION OVER THE LIFE COURSE Susan Howlett, Dalhousie University, Halifax, Nova Scotia, Canada
People age at different rates. This heterogeneity in aging has led to the concept of "frailty", a state of heightened vulnerability to adverse health outcomes at any age. Frailty challenges health care providers, as frail patients are more likely than non-frail patients to experience diseases, hospitalization, and death. We showed that frailty occurs not only in humans, but also in aging rodents. It can be measured with a "frailty index" (FI) based on age-related health deficit accumulation as originally established in humans. We found that maladaptive changes in heart structure and function in late life are correlated more so with frailty than age and are closely graded by FI score, especially in male mice. Adverse effects of frailty originate at cellular/subcellular levels and scale up to organ and system levels, predisposing towards cardiovascular disease. Poor overall health, quantified with an FI, may drive maladaptive cardiac remodeling, especially in older males.

RECRUITING ELIGIBLE AND INTERESTED STUDY PARTICIPANTS WITH COGNITIVE IMPAIRMENT Chair: Meghan Mattos Discussant: Jennifer Lingler
Recruiting and enrolling older adults with cognitive impairment is challenging under the best of circumstances. This symposium will begin with an introduction to best practices for recruitment of older adults living with cognitive impairment, followed by four presentations describing recruitment successes and challenges across multiple settings. The first presentation describes COVID-19 pandemic-related factors that have influenced recruitment and enrollment of older adults with cognitive impairment in an intervention study of a physical activity smartphone app. Strategies and procedural alterations to facilitate achievement of enrollment goals for technology-based interventions are discussed. The second presentation describes researchers' recruiting experiences with older adults with mild cognitive impairment (oaMCI)-care partner dyads for a pilot, platform trial of biopsychosocial interventions. There were differences in study disinterest between oaMCI and study partners that may require specialized communication messaging and strategies for dyad engagement. The third presentation features recruitment adaptations for an Internet-delivered behavioral intervention study with oaMCI and insomnia. Anticipated concerns of oaMCI using technology or accessing the Internet were not significant barriers to recruitment, while fewer oaMCI endorsed sleep concerns than expected. The last presentation demonstrates the potential for telephone-based outreach to increase dementia knowledge and cognitive risk. Working with faith-based health educators to reach rural, ethnically-diverse older adults, researchers will describe how to promote inclusivity and successfully recruit oaMCI within the community. Presenters and participants are encouraged to dialogue on how recruitment and retention barriers may be avoided as well as to share success stories from their own research with oaMCI. Clinical research involving participants with mild cognitive impairment (MCI) presents challenges to recruitment that may be further compounded by concerns when delivering a behavioral intervention via the Internet. The purpose of this talk is to describe recruitment adaptations for an Internet-delivered behavioral intervention study with older adults living with MCI and insomnia. Over the course of study recruitment, unforeseen barriers to recruitment were discovered, including fewer older adults with MCI endorsing sleep concerns than expected. The most substantive changes made to improve clinical recruitment were related to eligibility criteria, yielding 50% of the overall sample. Anticipated concerns of older adults with MCI using technology or accessing the Internet were not significant barriers to recruitment. Study findings support Internet-delivered intervention use in this population, which in the context of the COVID-19 pandemic, presents a potentially efficient and effective method for recruiting and delivering behavioral interventions in this difficult-to-enroll population.