The Pro-Aging Metabolic Reprogramming Hypothesis
There are a great many theories of aging. This is in part because it is easier to theorize than to develop concrete proof linking root causes to downstream effects in the biochemistry of aging. Cells are enormously complex systems, and tissues made up of cells are even more complex. Vast mountains of data relating to aging have been produced, layer upon layer of data, from changes in transcription to changes in cell behavior to changes in organ function to visible manifestations of age-related disease. Everything in the body interacts with everything else. Determining what is cause and what is effect is very challenging. So there is plenty of room for hypothesis, and most of those hypotheses will turn out to be wrong in some way.
Despite recent progress in understanding the biology of aging, the field remains largely fragmented due to the lack of a central organizing hypothesis that could provide a framework for investigating how fundamental upstream biological processes regulate the timing of age onset and progression. While numerous theories on aging have been proposed and efforts have been made to create unifying theories that incorporate various aging-related phenotypes and mechanisms, none of them constitutes a fully comprehensive doctrine for understanding the aging process in its entirety. There are ongoing debates on whether the aging process is programmed or stochastic. The programmed theory views aging as a continuation of the orderly genetic program that guides early growth and development, while the stochastic hypothesis considers aging to be a result of the accumulation of random errors. However, neither theory can independently explain the complexity of aging.
The Pro-aging metabolic reprogramming (PAMRP) theory proposed here posits that aging is determined by degenerative changes in cellular metabolism that occur over time. Specifically, aging has both a programmed and stochastic nature, with its onset requiring both the preexistence of pro-aging substrate (PAS) buildup through degenerative metabolic alterations and the emergence of pro-aging triggers (PAT) induced by stochastic events. The convergence of PAS and PAT initiates metabolic reprogramming (MRP), predisposing the body to cellular reprogramming (CRP) and genetic reprogramming (GRP) and ultimately leading to a self-perpetuating progression of the aging process governed by the genetic program.
The human body's metabolism is genetically preprogrammed but can be epigenetically reprogrammed for good or bad outcomes depending on the specific context. As organisms age, there are significant alterations in metabolic pathways within cells, including shifts in energy production, nutrient utilization, and waste-management processes. Initially, this MRP serves as an adaptive mechanism to cope with varying stress conditions. However, these adaptations come at the cost of accumulating molecular damage, including oxidative stress-induced DNA mutations, protein aggregation, and mitochondrial dysfunction, which are hallmarks of and substrates for aging. Over time, this MRP becomes maladaptive, contributing to a self-perpetuating cycle that maintains the altered metabolic state and exacerbates degenerative changes in gene expression and regulatory mechanisms. Ultimately, once a threshold level is reached, MRP triggers the genetic aging program, impacting cellular function, tissue homeostasis, and overall organismal health.