Exp Gerontol. Reinald Pamplona et al.

The strong interest shown in the study of the causes of aging in recent decades has uncovered many mechanisms that could contribute to the rate of aging. These include mitochondrial ROS production, DNA modification and repair, lipid peroxidation-induced membrane fatty acid unsaturation, autophagy, telomere shortening rate, apoptosis, proteostasis, senescent cells, and most likely there are many others waiting to be discovered. However, all these well-known mechanisms work only or mainly at the cellular level. Although it is known that organs within a single individual do not age at exactly the same rate, there is a well-defined species longevity. Therefore, loose coordination of aging rate among the different cells and tissues is needed to ensure species lifespan. In this article we focus on less known extracellular, systemic, and whole organism level mechanisms that could loosely coordinate aging of the whole individual to keep it within the margins of its species longevity. We discuss heterochronic parabiosis experiments, systemic factors distributed through the vascular system like DAMPs, mitochondrial DNA and its fragments, TF-like vascular proteins, and inflammaging, as well as epigenetic and proposed aging clocks situated at different levels of organization from individual cells to the brain. These interorgan systems can help to determine species longevity as a further adaptation to the ecosystem.