In Search for a Working Hypothesis of the Key mechanism(s) of Aging
Since the discoveries invoked above, the interest in the molecular pathways that control aging has exploded. In this perspective, many mutations in metabolic pathways have been shown to affect lifespan in different model systems, ranging from yeast to mice. Studies suggest that new pathways are even more relevant for human lifespan. Among others, maintenance of mitochondrial function has been suggested to be a key mechanism of extending lifespan, as decreased mitochondrial function, impaired ATP generation and increased reactive oxygen species (ROS) levels have all been shown to be implicated in driving the aging process (Guarente L. Mitochondria: a nexus for aging, calorie restriction, and sirtuins? Cell. 2008;132:171–176. Full Article) (Source)
To further complexify the issue, it has been shown that an increase in ROS can actually be a good thing for longevity. This idea has now gathered a large body of supportive evidence showing that repetitive mild stress exposure has anti-aging effects. (Rattan, Suresh I.S. (2008). “Hormesis in aging”. Ageing Research Reviews. 7 (1): 63–78. (Source) See also: Gems, David; Partridge, Linda (2008). “Stress-Response Hormesis and Aging: “That which Does Not Kill Us Makes Us Stronger””. Cell Metabolism. 7 (3): 200–3. (Source)
On the other hand, other scientists have shown that mitochondrial dysfunction is less the driver of aging than telomere shortening.
“The new findings demonstrate that the telomere dysfunction and activation of p53 also trigger a wave of cellular and tissue degeneration that links telomeres to well-known mechanisms of aging that are not simply related to rapid growth and division. In other words, telomere dysfunction is not just one culprit in the declining health of advanced age. It’s the kingpin, according to DePinho and his colleagues. In addition, the process weakens the body’s antioxidant defenses against the damaging molecules known as reactive oxygen species, or “free radicals,” that accumulate with age and exposure to stress. Until now, some researchers had labeled the decline in mitochondria or the buildup of free radicals as the primary causes of age-related ills. The new work integrates these seemingly disparate mechanisms into one unified theory of aging. Telomere dysfunction causes this wave of metabolic and organ failure, the scientists found, because when the p53 gene is activated, it represses the functions of two master regulators of metabolism, PGC1-alpha and PGC1-beta. (…) “This is the first study that directly links telomere dysfunction to regulators of the mitochondria and antioxidant defense via p53,” DePinho said. “The discovery of this new pathway of aging integrates a lot of different ideas people have had and gives us a better understanding of the aging process.” (Source)
And since these above-mentioned findings, still new discoveries have been made, many of which continue to either contradict and-or fine-tune the current model of aging. Now it would appear that telomere shortening is not the core mechanism since we can find animals that are long-lived with short telomeres and vice versa, short lived animals with long telomeres, including with the nematodes.
“Despite the close correlation of telomere length and clonal cellular senescence in mammalian cells, nematodes with long telomeres were neither long lived, nor did worm populations with comparably short telomeres exhibit a shorter life span. Conversely, long-lived daf-2 and short-lived daf-16 mutant animals can have either long or short telomeres. Telomere length of post-mitotic cells did not change during the aging process, and the response of animals to stress was found independent of telomere length. Collectively, our data indicate that telomere length and life span can be uncoupled in a post-mitotic setting, suggesting separate pathways for replication-dependent and -independent aging. (Source)
Even though mitochondrial homeostasis impairment is clearly associated with aging, the high complexity of aging phenotypes, and their underlying molecular mechanisms, make the deciphering of the real causing elements difficult. Moreover, the discovery of mitohormesis in stress response and ROS signaling pathways nuanced the idea of active and healthy mitochondria, and of ROS production and oxidative stress. Indeed, as described above, increased ROS and less active mitochondria can promote healthy aging and long lifespan. Likewise with telomerase enhancement and other pathways.
The Workshop’s Guiding Hypothesis on a unified theory of aging
While seemingly disparate, all of the aging mechanisms we have reviewed are inter-connected. Affecting one affects others. However, in all synergistic systems, there is usually a core pathway, a Kingpin that prevails over the other pathways. Biogerontoligist spend much of their time trying to ascertain this core. If and when such a core will be established and replicated, with solid evidence, that humans can optimize their lifespan to 120 years with few if any chronic diseases by significantly rejuvenating the key biomarkers of aging, then Biogerontologists will have decoded the correct Unified Theory of Aging and will hence be entitled to a deserved retirement.
For now, the Happiness Medicine Institute’s working hypothesis derives from what we have advanced so far, in particular that the organismal process of aging and perhaps life itself appear to be strongly influenced if not governed by an ancestral bacteria, the mitochondria, whose intelligence wiggled itself into an eukariotic cell and thanks to its small genome, cross talked with the eukariotic cell’s own nuclear genes for the synergistic benefit of both entities (the eukariotic cell and the mitochondria), thanks to which Life and it’s maintenance were able to fine-tune from billions of years ago to today. After many millions of years, this process evolved in millions of different Life forms, including human life.
Because most of the other important aging pathways we have examined are also under the strong influence of the mitochondria, in particular senescent cells, the P53 and stem cells, we therefore hypothesize that the central key to optimal longevity lies within both the mitochondria’s genome and its oxidative phosphorylation & ATP system as well as the mitochondria’s brethren, within the microbiota and the nDNA-mtDNA circuit or axis.
Indeed, the mitochondria appears to be key, we have seen this in carcinogenesis (see the Institute’s ACR research) and now we see this in the very processes of biological aging. With the endocannabinoid system, inter alia, the mitochondria has a central position in cell homeostasis of almost every tissue. (Boengler K., Kosiol M., Mayr M., Schulz R., Rohrbach S. Mitochondria and ageing: Role in heart, skeletal muscle and adipose tissue. J. Cachexia Sarcopenia Muscle. 2017;8:349–369. (Source). The mitochondria are not only responsible for the cell’s energy production and homeostasis, they are also responsible for phospholipids and heme, calcium homeostasis, apoptotic activation and inter alia, cell death. (Source) Thus, as far as the description of molecular and cellular mechanisms are concerned, mitochondria have been shown to participate in every main aspect of aging: decline of stem cell functions, cellular senescence, “inflammaging” and many others (Sun N., Youle R.J., Finkel T. The Mitochondrial Basis of Aging. Mol. Cell. 2016;61:654–666. (Source) The role of mitochondria in metabolic pathways, in particular with regard to caloric restriction and, inter alia, aerobic exercise is also relevant (Payne B.A., Chinnery P.F. Mitochondrial dysfunction in aging: Much progress but many unresolved questions. Biochim. Biophys. Acta. 2015;1847:1347–1353. (Source).
Traditionally, nDNA and mtDNA pathways have been viewed largely in isolation. (Per memory: mtDNA stands for mitochondrial DNA which spans about 16,500 DNA building blocks (base pairs), representing a small fraction of the total DNA in cells, 37 genes, all of which are essential for normal mitochondrial function and 13 of which provide instructions for making enzymes involved in oxidative phosphorylation). (Source)
However, recent studies have revealed a molecular circuit or axis that directly links DNA damage to compromised mitochondrial biogenesis and function via p53. These studies underscored the general importance of DNA integrity, as dysfunctional telomeres are recognized as DNA damage and activate the DNA damage response pathway, which leads to the activation of p53 (Source) p53, in turn, induces growth arrest, apoptosis and senescence in stem and progenitor cells (Source) Furthermore, there may even be an mTOR-Telomerase-Mitochondria connection. (Source)
The evidence therefore suggests that both DNA damage and metabolic pathways intersect and converge on mitochondria to compromise energy maintenance and drive aging as well as carcinogenesis (See below for the governing metabolic orgins of cancer). This integrated and holistic view provides an understanding of the mechanisms that control the fundamental process of aging. For now, this view will be this Workshop’s central working hypothesis that will guide us to the quintessence of what works in terms of optimizing rejuvenation to 120 years and beyond.