The Distinct Mechanisms of Aging Interact with One Another
Aging has a number of distinct root causes, but they do not proceed in isolation. Cell and tissue damage of one sort interacts with cell and tissue damage of other sorts, and so too do all of the downstream consequences of that damage. Aging is a web of connected issues, all making each other worse as they progress. Degenerative aging accelerates in pace over time precisely because of this behavior, in which damage and dysfunction speeds up the accumulation of more damage and dysfunction. The authors of the open access paper here illustrate this principle by taking mitochondrial dysfunction as a starting point and examining how it interacts with other known mechanisms of aging.
The role of mitochondrial dysfunction in aging is well documented. The primary hallmarks of aging are defined as unequivocally deleterious to the cell. This means that proper functioning of these processes is important for the viability of the cell and the dysfunction that occurs with age leads to cellular damage. Mitochondrial dysfunction interacts with each of these primary hallmarks, thus leading to progression of the aging process.
The nine cellular and molecular hallmarks of aging are divided into three groups; (a) the primary hallmarks, (b) antagonistic hallmarks, and (c) integrative hallmarks. The primary hallmarks, which are unequivocally deleterious to the cell, include genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis. The antagonistic hallmarks, which are beneficial at low levels but at high levels become deleterious, are deregulated nutrient sensing, cellular senescence, and mitochondrial dysfunction. Finally, the integrative hallmarks, affecting tissue homeostasis and function, are stem cell exhaustion and altered intercellular communication. These hallmarks of aging have been presented throughout various research disciplines as nine separate hallmarks, and, while possessing crosstalk, are still considered largely independent. In this review, we provide evidence of the interplay between hallmarks, by highlighting one, mitochondrial dysfunction, and how it interacts with all others.
The hallmarks of aging connect to and influence one another. For instance, cellular senescence can be induced by genomic instability or telomere attrition and epigenetic alternations can lead to genomic instability. It is hence evident that the hallmarks of aging are not discrete entities as how are often presented, but instead operate in a large and tightly connected network. Targeting one factor of this network can result in affecting other hallmarks and thus influence the whole network of aging.
Although this complicates our interpretation of anti-aging interventions and requires a more holistic approach, it also opens opportunities for treatment options that not only target one hallmark but in fact act on the entire, or at least a large section of the network. In relation to the phylogenetic tree of life, while the exact details of the hallmarks of aging may differ, the main commonality that unifies aging across all species is the fact that all their hallmarks interconnect. Taking the entirety of this network into account will benefit the aging research community, and ultimately allow for a greater understanding of the aging processes and the progression of age-related disease.