A recent article provides an integrative view of the hallmarks of aging and the extensive network linking them: time to join-up our thinking?
Mitochondria are cytosolic organelles found in the vast majority of eukaryotic cells. Through oxidative metabolism, mitochondria produce most of the energy of cells and are rightfully called the “power plants” of cells. Cell growth, DNA replication, gene expression and protein synthesis are energy-consuming cellular processes key for the maintenance of life. Hence, life as we know it could not exist without mitochondria, and mitochondrial dysfunction can cause numerous human diseases .
Longevity.Technology: The importance of mitochondria in aging and Longevity is increasingly being recognised, and mitochondrial dysfunction is now considered as one of the nine cellular hallmarks of aging, along with telomere erosion, cellular senescence, deregulated nutrient sensing, epigenetic alterations, loss of proteostasis, genomic instability, stem cell exhaustion, and altered intercellular communication. The hallmarks were first described in 2013 and are key to understanding the mechanisms of aging and identifying pharmaceutical targets to promote Longevity .
Since the first report of the hallmarks of aging, they are often studied as isolated events, and studies exploring the crosstalk between these hallmarks are limited. In an effort to provide a holistic insight into the multiple mechanisms involved in cellular dysfunction during aging, Sanne van der Rijt et al.  classified the hallmarks of aging into three categories: primary, antagonistic and integrative hallmarks of aging.
In this review article published in Frontiers in Cell and Developmental Biology, the authors describe the relevance of mitochondria in each of the hallmarks of aging. By regulating the primary hallmarks, mitochondrial dysfunction significantly impacts cell viability. Importantly, accumulation of reactive oxygen species (ROS) produced by mitochondria during oxidative phosphorylation can cause telomere erosion, epigenetic alternations, genomic instability, and proteostasis collapse—all of which can lead to cell death. In turn, epigenetic alterations worsen mitochondrial dysfunction by dysregulating the expression of mitochondrial proteins.
Accumulation of reactive oxygen species (ROS) produced by mitochondria during oxidative phosphorylation can cause telomere erosion, epigenetic alternations, genomic instability, and proteostasis collapse—all of which can lead to cell death.
The antagonistic hallmarks of aging – defined as hallmarks with beneficial or detrimental effects depending on their intensity – are also regulated by mitochondria. For example, cellular senescence can result from ROS accumulation and mitochondrial DNA damage and oxidative phosphorylation (OXPHOS). Aberrant nutrient sensing, the second antagonistic hallmark of aging, can lead to mitochondrial dysfunction and impairs mitophagy.
By interacting with integrative hallmarks of aging, mitochondrial dysfunction also affects tissue homeostasis. Mitochondrial dysfunction causes stem cell exhaustion mediated by ROS and OXPHOS. Intercellular communication alterations can also result from mitochondrial dysfunction, contributing to inflammaging and tissue dysfunction.
Notably, the authors highlight that most of these interactions between the hallmarks of aging are conserved across the tree of life – from fish to flies, worms, mice and humans!
Even though the mechanisms underlying individual hallmarks of aging are relatively well understood, increasing evidence suggests that extensive crosstalk occurs between these hallmarks, which can regulate one another. By providing an integrative view of the hallmarks of aging, this article provides an invaluable reference to the aging research community and highlights that holistic approaches are needed to combat aging.