Mitochondrial and energetic underpinnings of resilience in human aging: integrating genetic and epidemiological evidence

Geroscience proposes that an understanding of the basic biology of aging will lead to interventions on the aging process which can thereby reduce the risk of many major age-related diseases. One of the main challenges in Geroscience has been linking our biological knowledge of the hallmarks of aging to broad, aging- related health outcomes, and to operational metrics and interventions in humans. Altered mitochondrial biology – more specifically, diminished oxidative phosphorylation (OxPhos) capacity – is a core hallmark of aging, but is currently difficult to measure in clinical and epidemiological studies. There is good reason to think that diminished energetic capacity resulting from altered mitochondrial biology could lead to diminished resilience, but almost no work has been done to link the two. Here, we will leverage two unique human datasets – the MiSBIE study, which includes patients with and without severe, genetically determined mitochondrial disease, and BLSA, one of the longest-running cohort studies of aging – to assess the links between OxPhos capacity and resilience. Both contain detailed mitochondrial phenotyping and detailed stimulus-response protocols that permit us to measure resilience. In Aim 1 we will test for links between OxPhos capacity and resilience in both datasets. An exploratory sub-aim will derive novel, proteomics-based metrics of resilience, which can also be tested. In Aim 2, we will study GDF15 and FGF21 signaling pathways that may link altered mitochondrial biology to its downstream effects in the organism. In Aim 3, we will derive a novel “mito-health clock” that can be deployed in epidemiological and clinical studies as a proxy for much more expensive and challenging measurements of mitochondrial biology. Triangulation between genetic and epidemiological evidence will permit strong inference about how altered mitochondrial biology may cause changes in resilience. Key deliverables include: (1) The mito-health clock; (2) An understanding of how diminished OxPhos capacity determines resilience; (3) Identification of signaling signatures of OxPhos capacity in key mitokines, namely GDF15 and FGF21; and (4) Novel metrics of resilience based on proteome dynamics. Together, these results will mark a pivot point in our ability to study mitochondrial biology at the population level, greatly democratizing and accelerating our ability to test interventions and identify protective and risk factors related to mitochondrial biology and/or affecting resilience. Project Number: 1R01AG092819-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Alan Cohen | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $690,865 | Activity Code: R01 | Study Section: Aging, Injury, Musculoskeletal, and Rheumatologic Disorders Study Section[AIMR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11295976