Relevant to the goal of slowing or reversing aging, a broad panoply of evidence points to the need to control the chronic inflammation that is characteristic of aged tissues. Constant, unresolved inflammatory signaling actively disrupts tissue structure and function, changing cell behavior for the worse. It is likely the largest part of the way in which lingering senescent cells provide their contribution to the aging process, and many other forms of cellular dysfunction observed in aging can also generate inflammatory reactions. The contribution of senescent cells to the chronic inflammation of aging will likely be the easiest to control: simply destroy these errant cells. Other processes occurring inside the cells in aged tissues may be more challenging to rein in, such as the mislocalization of nuclear DNA and mitochondrial DNA, triggering innate immune mechanisms that evolved to react to the presence of bacteria and viruses.
Understanding the mechanisms of geroprotective interventions is central to aging research. We compare four prominent interventions: senolysis, caloric restriction, in vivo partial reprogramming, and heterochronic parabiosis. Using published mice transcriptomic data, we juxtapose these interventions against normal aging. We find a gene expression program common to all four interventions, in which inflammation is reduced and several metabolic processes, especially fatty acid metabolism, are increased. Normal aging exhibits the inverse of this signature across multiple organs and tissues.
A similar inverse signature arises in three chronic inflammation disease models in a non-aging context, suggesting that the shift in metabolism occurs downstream of inflammation. Chronic inflammation is also shown to accelerate transcriptomic age. We conclude that a core mechanism of geroprotective interventions acts through the reduction of inflammation with downstream effects that restore fatty acid metabolism. This supports the notion of directly targeting genes associated with these pathways to mitigate age-related deterioration.