A decline in glycolytic ATP production is the fundamental mechanism limiting lifespan; species with an optimal rate of decline over time survived

Glycolytic ATP production declines with age, contributing to common aging phenotypes such as reduced cell division and impaired DNA & mitochondria repair. Notably, immortal cells exhibit a metabolic profile characterized by sustained, highly active glycolytic ATP production. A key unresolved question is the underlying mechanism driving the gradual decline in glycolytic ATP production during natural aging. We have found that this can be explained by the concept that a decline in glycolytic ATP production was crucial for survival of species, and only those species with an optimal rate of reduction in glycolytic ATP production over time were selected and persisted through generational changes. Sexual reproduction generates new combination of gene pairs with abundant DNA mutations during meiosis, which provides significant advantages in adapting to environmental changes and competence over other species. However, the population of species is limited because of finite food supply in the natural world. The shift from glycolysis to aerobic metabolism increases energy efficiency and the increased energy efficiency in parent generation benefits the species by enhancing survival of parent generation at starvation conditions and limited food allocation to the offspring generation. This conceptual framework can explain the finite lifespans of organisms, significant variations in lifespan across species, cellular immortality of cancer cells, and the exceptionally long life of the naked mole rat (<i>Heterocephalus glaber</i>). Although questions remain, this concept offers new insights into the biology of aging and potential strategies for rejuvenation therapies for humans.