ARE THERE GENETIC FACTORS UNDERLYING LONGEVITY?
The ability to live long lives is clearly heritable: children of parents who live exceptionally long, often live long themselves. Indeed centenarians (those who live to be age 100 years or more) can often be found in families. Centenarians avoid most age-related diseases (cardiovascular disease, dementia, cancer) and display very healthy metabolic profiles. Conversely, there are rare diseases that cause premature aging, such as Hutchinson- Gilford progeria, in which mutations present in the LMNA gene cause children to age very quickly. These children have wrinkled skin, heart disease, and characteristics of 80-year-olds; nearly all die before age 13. Another premature aging syndrome is the Werner syndrome, in which the gene encoding the WRN helicase is mutated. Werner patients also develop signs of premature aging in their teenage years, with wrinkled skin, gray hair, and cataracts. Both extreme longevity (being a centenarian) and premature aging syndromes have been helpful for understanding the genetic factors that are important for aging. But a key step in pinpointing the genes involved in longevity came from studies in model organisms, where experiments on longevity can be conducted.
Nearly all organisms age. Interestingly, a few species, such as hydra or some species of clams (ocean quahog), show minimal aging. In fact, the latter can live to be over 500 years old (Figure 1)! Many model organisms that can be genetically manipulated, such as yeasts, worms, and flies, have been used to identify and study the genes that control aging. This has revealed conserved genes and pathways involved in longevity. For example, the insulin signaling pathway (the insulin receptor itself or the downstream FOXO transcription factors) is critical for the aging process. Interestingly, the insulin-FOXO pathway is conserved across species, and it regulates aging in many organisms, including mammals. Moreover, centenarians have specific genetic variations in genes from the insulin-FOXO pathway. Another pathway that has been shown to be central to aging is the mTOR pathway, which is involved in sensing nutrients, especially amino acids. Blocking the mTOR pathway has been shown to extend lifespan in yeast, worms, flies, and even mammals. Many other metabolic pathways that affect lifespan and healthspan (the portion of life without diseases) have been identified, including Sirtuins (protein deacetylases that are dependent on the metabolite cofactor called NAD+) and AMP-dependent protein kinase (AMPK) (a protein kinase that is dependent on the AMP to ATP ratio in cells). Metformin is a drug commonly used to control type 2 diabetes and an activator of AMPK; it can extend lifespan in mice as well as in people who are diabetic. Metformin has been recently proposed as an “antiaging” drug. Through further study of centenarians and other healthy long lived people, it is likely that more genes that extend human longevity will be uncovered.
Figure 1. Some species of clams do not seem to age. Unlike humans, the clam depicted at the top is estimated to be 507 years old. Clam image attribution: “Ming clam shell WG061294R” by Alan D. Wanamaker Jr., Jan Heinemeier, James D. Scourse, Christopher A. Richardson, Paul G. Butler, Jón Eiríksson, Karen Luise Knudsen Licensed under CC BY 3.0 via Wikimedia Commons.