Chapter 168
Changing Aging — 5
Especially intriguing is the profound slowing of aging in turtles, twentyfold slower than mammals and twice as slow as humans and birds. There is intense interest for learning more on the aging process through dogs, with a large open science Dog Aging project and UK Dogs Trust initiative. But all these vertebrates can’t compete with the immortality of jellyfish! Whole genome sequencing of the immortal jellyfish Turritopsis dohrnii, the only species to rejuvenate repeatedly after sexual reproduction, has demonstrated gene variants that are connected with most of the hallmarks of aging, including genomic instability, telomeres, mitochondrial dysfunction, stem cell exhaustion, intercellular communication, and cellular senescence.
Figure 12.2. Maximum lifespan of multiple species. Adapted from Param Priya Singh et al., “The genetics of aging: A vertebrate perspective,” Cell 177, no. 1 (March 2019): 200–220, https://doi.org/10.1016/j.cell.2019.02.038.
Telomeres
Throughout life there is a steady erosion to the tips of chromosomes, an attrition that is part of normal aging and consistent across all chromosomes of an individual. Once a cell’s telomeres get too short, it can no longer divide. But it’s a Goldilocks story since long telomeres (adjusted for age) predispose to cancer and short ones are linked to age-related diseases. The long telomere story is much akin to longer lifespan across species, promoting vulnerability, but here with a faster rate of accumulation of mutations. Many types of common cancers, and especially malignant melanoma, are seen at increased rates with long telomeres. There are adult-onset inherited short telomere syndromes that include premature hair graying, idiopathic (cause unknown) pulmonary fibrosis, and T cell immunodeficiency. The latter increases the risk of hematologic cancers such as myelodysplastic syndrome and acute myelogenous leukemia. In the mouse model, activation of telomeres by telomerase gene therapy inhibited pulmonary fibrosis. The recent discovery of a telomerase verse transcriptase activator compound is encouraging because it promoted telomere synthesis, blunted tissue aging hallmarks, and reduced brain inflammation, all without risk of cancer, in the mouse model.
Short telomeres also predispose to the accumulation of mutations in blood stem cells. This condition, known as clonal hematopoiesis of indeterminate potential (CHIP), is increasingly common with age and is associated with a higher rate of cardiovascular disease, blood clotting events, and chronic liver disease. The most common driver mutation in the blood cell clones is in DNMT3A, a gene that controls telomere length, which tells us how tightly CHIP and telomeres are intertwined. These heightened risks are believed to be due to promoting inflammation or the process of “inflammaging,” as documented in experimental models. Over 10 percent of people aged seventy and older have CHIP, and I have argued that the I for “indeterminate” now be dropped because these blood stem cell mutations carry a clear risk; it’s no longer fuzzy. I believe this condition should be routinely assessed in older adults as part of a comprehensive risk assessment to be integrated with all the multilayered data we’ve been reviewing throughout the book.