I had recently participated in a roundtable discussing the possibilities of clinical immortality. Some key aspects of the conversations deserve memorialization here as they relate closely to what I believe is possible both today and within the near future.
It is the premise of most age management physicians and scientists that aging results in an abnormal imbalance of anabolism and catabolism. As we grow and in our youth, anabolism either outdistances catabolism or keeps pace with it. At some point, we can no longer keep pace with the degradative properties of aging and we begin to lose the battle. The Hayflick Hypothesis refers to “replicative senescence” but I believe most of us fall prey to “premature senescence.” In this case, exogenous stressors bring physiological changes to bear which stress our systems beyond their abilities – ultimately yielding autoimmune diseases, cardiovascular disease, CNS disease, cancer, aging, and eventually death. The two biggest catabolic components are likely inflammation and poor redox homeostasis. For many years heart disease and stroke were linked primarily to lipid metabolism, but the last decade has seen a significant appreciation of the role of inflammation in these two entities. Similarly, we know all too well that aging compromises both the innate and adaptive immune systems. Memory B cells, T cells, neutrophils, and macrophages all decrease in effectiveness as father time marches by, further limiting our abilities to compensate with these inherent physiological changes. Finally, a new subset of medicine – age management medicine – has given rise to the understanding that we need energy to grow, repair, fend off infection/inflammation, and even fight cancer. At the heart of this therapy resides the main energy machines within our bodies – the mitochondria. Limited ability to produce energy (ATP/NADH), react to oxidative stress (reactive oxygen and nitrogen species) and dispose of damaged mitochondria (mitophagy) and other cellular debris (autophagy) are hallmarks of poor redox.
Previously, and throughout this chapter, I have alluded to all of the numerous ways that generic MSC EVs combat these changes. They produce numerous anti-inflammatory substances, promote the production of energy through the sharing of key enzymes in the ATP glycolytic pathway, and even contribute to improved mitophagy and autophagy. In fact, it has been shown that MSC EVs cause microglia in the CNS to secrete neprilysin – combating ß-amyloid plaques via endogenous proteolytic pathways in mouse models of Alzheimer’s disease. In mouse models of Parkinson’s Disease, α-synuclein, another protein aggregate molecule, showed improved intracellular clearance through an increase in autophagy after MSC introduction.
Much time has been spent painting the picture of resident stem cells and their relative quiescent state without the requisite “young blood” bathing their niches. If in fact it is the limited milieus throughout our bodies that inhibit our regenerative potential – then might it be possible to turn back aging with simple injections at given times throughout the year? Maybe the next steps will include broths rich in GDF11, miRNA 133b (neuroregeneration), miRNA 133a (cardiac regeneration) or similar substituents rich in the growth factors necessary to combat specific organ aging.
An interesting paper a few years ago by Joshua Schiffman, a pediatric oncologist at the University of Utah discussed the quandary known as Peto’s Paradox. They addressed the mismatch of organism size and cancer rates in elephants. Obviously, bigger organisms have greater chances for cells going awry – yet elephants do not get cancer. Maybe the answer lies in the tumor-suppressing gene P53. We have one copy – elephants have 20. Perhaps tomorrow’s exosomes will also be enriched in P53. In this way, we may someday obviate the need for the Trojan horse.
Writing Credit Doug Spiel MD, Chp 12, The Role of Exosomes…
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