Aging is the process of the decline of the physiological function of organs, which is thought to arise from both endogenous (i.e., cellular metabolism) and exogenous factors (i.e., air pollutants) that eventually lead to death. However, the exact spatiotemporal mechanisms that cause the decline in organisms are still unknown. Fortunately, extensive research has been done to elucidate how the decline happens and the biological cues that drive the aging process. A common convergence in the field of geroscience is the factors found in the circulatory system and their regenerative and, more commonly, deleterious effects. Pro-rejuvenating factors decline with age, and when replenished to youthful levels, they can restore function to the pathways that are dysregulated due to their depletion. Conversely, factors that have become deleterious due to deregulation can be reduced or inhibited to allow the organ's natural repair mechanisms to function to restore proper organ homeostasis. Both of these strategies may be used to reverse the age-associated decline of organ function and, ideally, extend both lifespan and healthspan, the time we live disease-free. However, considering the upregulation of many factors with age, and the even more numerous pathways disturbed by this upregulation, a more holistic approach would target these broader changes rather than merely attempting to restore, or more often, flood a single factor that decreases with age.Heterochronic blood exchange has emerged as a model to understand how the systemic milieu contributes to the aging process. Numerous individual factors have been discovered to contribute to the aging process when elevated, but the exact mechanism of how the old milieu exacerbates aging is largely unknown. By using a heterochronic blood exchange model, I showed an increase in senescent muscle stem cells in young mice after blood exchange with old mice. Moreover, after delivery of navitoclax, a common senolytic, to the old mouse prior to the blood exchange, the senescence transfer was no longer seen. This was verified using a second senolytic, dasatinib and quercetin. These results reinforce the idea that cellular senescence is not only a response to stress over a lifetime, but can be an immediate response from other senescent cells.
Pharmacological approaches for targeting pathogenic cells, such as cancer or senescent, have the capacity to revolutionize biomedicine, but these cells resist apoptosis, and high doses of drugs also harm healthy cells in a patient. It would be very useful to simultaneously eliminate senescent and cancer cells because the senescent niche supports cancer progression, but drugs that target proliferating cells do not work against senescent cells. Approaches for energy starvation of cancer have not yet met with clinical success; moreover, senolytic attributes of this direction are largely unknown, and metabolic similarities between senescence and cancer are not well understood. Here I define the shared metabolic shifts in cancer and senescence, and develop a novel formulation of dichloroacetate, metformin, and 10-fold reduced dose of BCL-2 inhibitor that critically diminishes respiratory spare capacity for ATP synthesis only in the senescent and cancerous cells, allowing their simultaneous targeting without damage to healthy cells. In vivo, this three-drug formulation, DMA, is rejuvenative in old mice, suggesting a broadly available solution to counteract senescence, cancer, and aging effectively and simultaneously without deleterious side effects.
