The study of the comparative biology of aging, and comparative biology more generally, is alive and well. A sizable community of researchers consider that the study of differences between long-lived and short-lived species is a good path to a better understanding of aging that may ultimately inform the development of life-extending therapies. Whether there is biochemistry in long-lived species that can be directly transferred into humans for benefit remains an open question; it may be that nothing is that simple, but the example of employing naked mole-rat cGAS to improve DNA repair is a promising example of the sort of gene therapies that may become possible in the future. Is all of this research proceeding in an optimal way, however? Here, a researcher argues for a greater emphasis on holistic comparisons between species of specific organelle structures inside the cell, such as mitochondria, rather than continuing to proceed gene by gene and protein by protein.
The past decade has defined molecular hallmarks of aging, yet interventions that extend lifespan in short-lived organisms show limited and context-dependent translation to humans. Comparative studies of exceptional longevity remain largely genome-centric, although genomic instability alone cannot comprehensively explain aging-related pathologies. Many age-associated failures emerge at the level of cellular organelles whose stability underpins tissue function. The pathways that sustain these structures operate through proteomic, metabolic, and lipid networks that are insufficiently captured by genomic or transcriptomic analyses.
Notably, longer organismal lifespan increases the requirement for sustained organelle functionality and fidelity. This Perspective proposes that the next conceptual advance in geroscience will come from comparative organelle biology. Examining mammals with divergent lifespans, including species evolutionarily closer to humans, can reveal how long-lived lineages evolved organelle-level architecture and resilience mechanisms that support cellular function over decades. I introduce the Comparative Metabolic Longevity Cell Atlas (CMLCA), a cross-mammalian platform integrating standardized cellular systems, organelle-resolved multi-omics, and computational analysis to identify conserved features of resilience and inform next-generation strategies to improve human healthspan.
Link: https://doi.org/10.1038/s44321-026-00428-2
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