Date of Award

Spring 5-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Computational & Systems Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Overall, my dissertation integrates longitudinal measurements of physiology to investigate the aging process. In the first half, I examine the surprising and largely unexplained degree of variation in lifespan within even homogeneous populations. I sought to understand how physiological aging differs between long- and short-lived individuals within a population of genetically identical C. elegans reared in a homogeneous environment. Using a novel culture apparatus, I longitudinally monitored aspects of aging physiology across a large population of isolated individuals. Aggregating several measures into an overall estimate of senescence, I find that long- and short-lived individuals start adulthood on an equal physiological footing. However, longer-lived individuals then experience slower declines in function, but spend a disproportionately large portion of life in poor physiological health. Indeed, the period of early-life good health is much less variable than the period of late-life advanced senescence, which I conclude to be a more plastic phase of life. In the second half, I show that simple physiological measurements have broader lifespan-predictive value than previously believed and that incorporating information from multiple time points can significantly increase that predictive capacity. Using longitudinal data from a cohort of 1349 human participants in the Framingham Heart Study, I show that as early as 28–38 years of age, almost 10% of variation in future lifespan can be predicted from simple clinical parameters. Further, different clinical measurements are predictive of lifespan in different age regimes. Moreover, I find that several blood glucose and blood pressure are best considered as measures of a rate of “damage accrual”, such that total historical exposure, rather than current measurement values, is the most relevant risk factor (as with pack-years of cigarette smoking). Together, this work has established the physiological basis of variation in longevity within an isogenic population of C. elegans and extended our ability to predict mortality from basic clinical measurements in humans.

Language

English (en)

Chair and Committee

Zachary Pincus

Committee Members

Gautam Dantas, Todd Druley, Shin-ichiro Imai, Gary Stormo,

Comments

Permanent URL: https://doi.org/10.7936/vbn7-2c28

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