Pankaj Kapahi

All Publications

• Why studying females reveals more about aging: The reproductive resilience hypothesis for the evolution of sex-specific aging. Cell Singh, P., Tanwar, V., Xiang, Y., Enriquez Najera, L., Austad, S. N., Kapahi, P. 2026; 189 (16): 4832-4856

  Abstract

  Classical evolutionary theories of aging, including antagonistic pleiotropy (AP) and the disposable soma theory (DST), explain why aging exists but are often applied without considering how sex-specific reproductive strategies shape the forces of natural selection on survival. They do not explain why females consistently outlive males across taxa, despite their greater reproductive investment, or why in some contexts, such as eusocial queens, extraordinary fecundity is coupled with exceptional longevity. To explain these patterns, we propose the reproductive resilience hypothesis (RRH), which posits that when reproductive success depends on prolonged survival and caregiving, natural selection favors coupling reproduction with enhanced somatic maintenance rather than trading it off. We suggest that reproductive events, including age at sexual maturity, pregnancy, lactation, and menopause, are pivotal life-history transitions and must be explicitly integrated into studies of sex differences that drive aging and susceptibility to age-related diseases. We further propose that loss of reproductive resilience is a sex-specific hallmark of aging that coordinates the emergence of multiple downstream hallmarks, helping explain the acceleration of systemic aging and age-related disease following reproductive decline. We propose that, for these reasons, studying females should be prioritized, as it has unique implications for discovering pathways to slow aging and prevent age-related diseases, ultimately benefiting both women and men.

  View details for DOI 10.1016/j.cell.2026.07.013

  View details for PubMedID 42561912

• Glycation-lowering compounds inhibit ghrelin signaling to reduce food intake, lower insulin resistance, and extend lifespan. Cell reports Wimer, L. A., Kaneshiro, K. R., Ramirez, J., Bose, N., Valdearcos, M., Shanmugam, M. M., Farrera, D. O., Singh, P., Beck, J., Sellegounder, D., Najera, L. E., Melov, S., Ellerby, L. M., Cho, S. J., Newman, J. C., Koliwad, S., Galligan, J. J., Kapahi, P. 2025; 44 (10): 116422

  Abstract

  Non-enzymatic reactions in glycolysis produce methylglyoxal (MGO), a reactive precursor to advanced glycation end-products (AGEs), which has been hypothesized to drive obesity, diabetes, and aging-associated pathologies. A combination of nicotinamide, α-lipoic acid, thiamine, pyridoxamine, and piperine (Gly-Low) lowers the deleterious effects of glycation by reducing MGO and the MGO-derived AGE, MG-H1, in mice. Gly-Low supplementation in the diet reduces food consumption, decreases body weight while preserving muscle mass, improves insulin sensitivity, and increases survival in leptin receptor-deficient (Leprdb) and wild-type C57B6/J mice. Transcriptional, protein, and functional analyses demonstrate that Gly-Low inhibits appetite stimulation through ghrelin and AMP-activated protein kinase (AMPK) signaling pathways in the hypothalamus, leading to reduced hunger responses. Consistent with these molecular findings, Gly-Low inhibits ghrelin-mediated hunger responses. As a late-life intervention, Gly-Low slows hypothalamic aging signatures, improves glucose homeostasis and motor coordination, and increases lifespan, suggesting its potential benefits in ameliorating age-associated decline.

  View details for DOI 10.1016/j.celrep.2025.116422

  View details for PubMedID 41086114

  View details for PubMedCentralID PMC12626231

• Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction. Nature metabolism Bar, S., Wilson, K. A., Hilsabeck, T. A., Alderfer, S., Dammer, E. B., Burton, J. B., Shah, S., Holtz, A., Carrera, E. M., Beck, J. N., Chen, J. H., Kauwe, G., Seifar, F., Shantaraman, A., Tracy, T. E., Seyfried, N. T., Schilling, B., Ellerby, L. M., Kapahi, P. 2025; 7 (7): 1375-1391

  Abstract

  Tauopathies encompass a range of neurodegenerative disorders, such as Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau inclusions (FTLD-tau), for which there are currently no successful treatments. Here, we show impaired glycogen metabolism in the brain of a tauopathy Drosophila melanogaster model and people with AD, indicating a link between tauopathies and glycogen metabolism. We demonstrate that the breakdown of neuronal glycogen ameliorates the tauopathy phenotypes in flies and induced pluripotent stem cell (iPSC)-derived neurons from people with FTLD-tau. Glycogen breakdown redirects glucose flux to the pentose phosphate pathway and alleviates oxidative stress. Our findings uncover a critical role for the neuroprotective effects of dietary restriction (DR) by increasing glycogen breakdown. Mechanistically, we show a potential interaction between tau protein and glycogen, suggesting a vicious cycle in which tau binding promotes glycogen accumulation in neurons, which in turn exacerbates tau accumulation which further disrupts cellular homeostasis. Our studies identify impaired glycogen metabolism as a key hallmark for tauopathies and offer a promising therapeutic target in tauopathy and other neurodegenerative diseases.

  View details for DOI 10.1038/s42255-025-01314-w

  View details for PubMedID 40588539

  View details for PubMedCentralID PMC12795109

• OXR1 maintains the retromer to delay brain aging under dietary restriction. Nature communications Wilson, K. A., Bar, S., Dammer, E. B., Carrera, E. M., Hodge, B. A., Hilsabeck, T. A., Bons, J., Brownridge, G. W., Beck, J. N., Rose, J., Granath-Panelo, M., Nelson, C. S., Qi, G., Gerencser, A. A., Lan, J., Afenjar, A., Chawla, G., Brem, R. B., Campeau, P. M., Bellen, H. J., Schilling, B., Seyfried, N. T., Ellerby, L. M., Kapahi, P. 2024; 15 (1): 467

  Abstract

  Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects. Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function of OXR1 variants. Multi-omic analyses in flies and humans showed that decreased Mtd/OXR1 is associated with aging and neurological diseases. mtd/OXR1 overexpression rescued age-related visual decline and tauopathy in a fly model. Hence, OXR1 plays a conserved role in preserving retromer function and is critical for neuronal health and longevity.

  View details for DOI 10.1038/s41467-023-44343-3

  View details for PubMedID 38212606

  View details for PubMedCentralID PMC10784588

• Dietary restriction and the transcription factor clock delay eye aging to extend lifespan in Drosophila Melanogaster. Nature communications Hodge, B. A., Meyerhof, G. T., Katewa, S. D., Lian, T., Lau, C., Bar, S., Leung, N. Y., Li, M., Li-Kroeger, D., Melov, S., Schilling, B., Montell, C., Kapahi, P. 2022; 13 (1): 3156

  Abstract

  Many vital processes in the eye are under circadian regulation, and circadian dysfunction has emerged as a potential driver of eye aging. Dietary restriction is one of the most robust lifespan-extending therapies and amplifies circadian rhythms with age. Herein, we demonstrate that dietary restriction extends lifespan in Drosophila melanogaster by promoting circadian homeostatic processes that protect the visual system from age- and light-associated damage. Altering the positive limb core molecular clock transcription factor, CLOCK, or CLOCK-output genes, accelerates visual senescence, induces a systemic immune response, and shortens lifespan. Flies subjected to dietary restriction are protected from the lifespan-shortening effects of photoreceptor activation. Inversely, photoreceptor inactivation, achieved via mutating rhodopsin or housing flies in constant darkness, primarily extends the lifespan of flies reared on a high-nutrient diet. Our findings establish the eye as a diet-sensitive modulator of lifespan and indicates that vision is an antagonistically pleiotropic process that contributes to organismal aging.

  View details for DOI 10.1038/s41467-022-30975-4

  View details for PubMedID 35672419