Centenarians, people who survive to 100 years of age or more, are comparatively resistant to age-related disease. They are not in good shape in comparison to a much younger person, of course. They are much reduced in vigor and capacity, and aging has gnawed away at their bodies and minds. But nonetheless, the very modest goals of much of the aging research community – to slow aging and extend healthy life span by just a few years – leads to the view that centenarian biochemistry is an interesting place to look for the basis for treatments. If the goal is only a couple more years of life, then why not investigate how it is that some people manage to live a decade or more longer than their peers? If the goal is to achieve far greater results, however, meaning actual rejuvenation, reversal of aging, extending healthy and youthful life spans by decades or more, then we must look elsewhere, towards mechanisms and tools that do not naturally occur in the human body.
Although human life expectancy has increased over the past two decades, individuals in most countries do not appear to be living healthier. Disease prevalence, disability, and the number of years spent with disease or disability have all increased. Yet, in contrast, many centenarians do not follow this trend. Rather, exceptional longevity is associated with a reduced risk of morbidity and, on average, a delay in the onset of age-associated diseases including cancer, cardiovascular disease, stroke, and dementia. Throughout older adulthood, in comparison to their peers who do not survive to 100 years, centenarians have fewer diseases and limitations in performing activities of daily living and are less likely to be hospitalized. Moreover, living to extreme ages has been associated with compression of morbidity and disability, or shortening the proportion of life spent with disease and disability toward the end of life. In fact, supercentenarians, individuals aged 110+ years, spend only 5% of their lives on average with an age-related disease in comparison to 18% for younger controls with many maintaining functional independence up to the age of 100 years.
The exceptionality of centenarians (i.e., their extreme survival), is the reason that they are a powerful cohort among which to examine genetic contributions to longevity and healthy aging. The sensitivity of a genetic risk model to correctly classify individuals as long-lived increased with increasing age exceptionality (i.e., 71% specificity in classifying individuals aged older than 102 years and 85% specificity in classifying individuals aged older 105 years) indicating that the genetic contribution to longevity becomes stronger when looking at older ages. The ability to reach exceptional ages without an age-related disease is also considered an extreme phenotype which can increase the power to identify genetic variants associated with a reduced risk of disease. Using centenarians as extreme controls against cases with specific age-related diseases has been shown to increase the power to detect associations between genetic variants and risk of disease.
Unexpectedly it seems that centenarians do not achieve their exceptional longevity due to the absence of genetic variants associated with disease, as centenarians have been found to have variants related to increased risk of cancer, cardiac disease, and even neurodegenerative diseases. Rather, it seems that centenarians are enriched with protective genes, including variants related to a reduced risk of cardiovascular disease and hypertension as well as enhanced immunity and metabolism. Genetic comparisons with centenarians may also be helpful in evaluating the clinical significance of genetic variants found to be associated with disease as those that are present in centenarians clearly do not preclude long survival.