The evolution of asymmetrical regulation of physiology is central to aging

Abstract: The evolutionary biology of aging is fundamental to understanding the mechanisms of aging and how to develop anti-aging treatments. Thus far most evolutionary theory concerns the genetics of aging with limited physiological integration. Here we present an intuitive evolutionary framework built on how physiology is regulated and how this regulation itself is then predicted to age. Life has evolved to secure reproduction and avoid system failure in early life, and it is the physiological regulation that evolves in response to those early life selection pressures that leads to the emergence of aging. Importantly, asymmetrical regulation of physiology will evolve as the Darwinian fitness costs of loss of regulation will not be symmetrical. When asymmetrical regulatory systems break during aging, they cause physiological function to drift towards the physiological range where costs of dysregulation are lowest, rendering aging directional. Our model explains many puzzling aspects of the biology of aging. These include why aging appears (but is not) programmed, why aging is gradual yet heterogeneous, why cellular and hormonal signaling are closely related to aging, the compensation law of mortality, why trade-offs between reproduction and aging remain elusive, why longer-lived organisms show more signs of aging during their natural lifespans, and why longer-lived organisms can be less responsive to treatments of aging that work well in short-lived organisms. We provide predictions of our theory that are empirically testable. By incorporating physiological regulation into evolutionary models of aging, we provide a novel perspective to guide empirical research in this still growing field.