Age-onset diseases including cancer, neurodegenerative disease, diabetes, cardiovascular disease, stroke, and osteoporosis are generating a public health burden that is quickly becoming insurmountable. Exacerbating this problem, co-morbidities are common among the elderly. The ideal therapeutic strategy to confront this crisis is to target a unifying risk factor, but patient age is the only risk factor common to all these diseases. Fortunately, it is increasingly clear that the biological processes of aging are malleable, thus the rate and quality of aging may be improved. Genetic and nutritional interventions causing real or perceived energy- depletion are robust, conserved mechanisms to promote healthier aging. Unfortunately these interventions, e.g. activation of the molecular low-energy sensor AMPK, also carry clinically unacceptable side effects, such as suppressed immunity and fertility. Translating these findings into therapeutics thus requires identification of downstream mechanisms that are sufficient for healthier aging. Through a genetic model of longevity in C. elegans via activation of AMPK, we demonstrated that the negative side-effects of energy-depletion can be uncoupled from the positive effects on healthy aging. Using unbiased, systems-level approaches, we found that the longevity-specific mechanism involves downstream regulation of mitochondrial dynamics and metabolic functions, and we now demonstrate that regulation of mitochondrial dynamics is causal to AMPK longevity. New data indicate that perturbing the unfolded protein response (UPR), which mediates homeostasis of the endoplasmic reticulum (ER), interacts with the AMPK pathway to extend lifespan through a mechanism that also requires mitochondrial remodeling. Given recent studies showing that the ER physically interacts with mitochondria to regulate organelle morphology and metabolic signaling, these data suggest a new paradigm in aging: ER/mitochondrial regulation of longevity occurs through an integrated metabolic mechanism. Physical changes in mitochondrial networks are a hallmark of aging, but how organelle dynamics are mechanistically involved in longevity is unknown. By genetically inactivating mediators of mitochondrial remodeling (fission/fusion), Aim 1 will define how mitochondrial dynamics drive the changes in mitochondrial metabolism associated with low-energy longevity. Through novel transgenics and training in high-resolution microscopy in Aim 2, I will test the hypothesis that UPRER perturbations promote altered mitochondrial morphology and signaling between organelles. Finally in the R00 phase, Aim 3 will build on the tools and insights developed in Aims 1 and 2 to identify genetic mechanisms in C. elegans by which ER-mitochondrial inter-organelle communication can be directly targeted to extend healthy lifespan and protect metabolic homeostasis. Taken together, the goal of this proposal is to identify how evolutionarily conserved energy-sensing pathways coordinately modulate inter-organelle signaling and metabolic function to promote longevity.

Public Health Relevance

Genetic and dietary interventions causing real or perceived energy-depletion protect against diverse age-onset diseases and morbidity, but carry clinically unacceptable side effects preventing therapeutic development. The proposed studies build on a preliminary discovery that the positive effects on healthy aging are mechanistically achieved through altered mitochondrial behavior and metabolism, and can be uncoupled from negative side- effects on reproduction, growth, etc. The Aims of this proposal are designed to identify novel molecular mechanisms at the subcellular level by which mitochondria interact with other organelles to shape metabolism and how these can be targeted to protect against the rapidly growing public health burden of age-related pathologies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Career Transition Award (K99)
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Biological Aging Review Committee (NIA-B)
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Fridell, Yih-Woei
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Harvard University
Schools of Public Health
United States
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Weir, Heather J; Yao, Pallas; Huynh, Frank K et al. (2017) Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell Metab 26:884-896.e5