Fight Aging!

Verifying the ages of those who claim to be extremely old is rarely as easy might be the case. Many parts of the world are lacking any sort of suitable records infrastructure dating back far enough to help. Particularly past the age of 110, the small number of verified individuals makes any attempt to learn from epidemiological data quite difficult. This in today's open access paper, researchers here report on the construction of epigenetic clocks using data from the oldest living people, with the hope of producing a tool that can help to verify claims of exceptional old age, and thus expand the databases.

While this is certainly interesting science, and will hopefully solve a logistical problem for other scientists, it is far from clear the study of survival to extreme old age will actually teach us anything useful. Long-lived individual share their gene variants and biochemistry with countless others who didn't make it. If a given variant gene doubles the ~1% chance of living to 100 for someone born a century ago, then you will see a lot of centenarians with that variant, but their survival is still overwhelmingly a matter of luck in the random distribution of life expectancy. Further, centenarians are not in good shape, and supercentenarians even less so, with a ~50% yearly mortality rate and greatly diminished physical capabilities. This is not the outcome that we should be seeking to emulate in later life.

Centenarian clocks: epigenetic clocks for validating claims of exceptional longevity

Clouding this debate over limits to human lifespan is poor record keeping in the early twentieth century, and extreme age claims made for secondary gain. Norris McWhirter of the Guinness Book of World Records, wrote, "No single subject is more obscured by vanity, deceit, falsehood, and deliberate fraud than the extremes of human longevity". Mistakes in age claims can also arise due to dementia or confabulations. The maximum life span of humans is currently determined by Jeanne Calment, documented to have lived for 122 years. Controversy still exists over Jeanne Calment's age despite verified documentation. Although a sample of her blood is stored and analyses might help resolve the controversy, to date, it has not been allowed due to ethical constraints surrounding the informed consent signed at the time of sample donation. Even with proper documentation, Jeanne Calment's age is doubted because documentation alone can be falsified or misattributed to an heir as some have suggested

Highly accurate age estimators can be built based on DNA methylation levels. The high accuracy of epigenetic clocks has been replicated numerous times and would be one way to verify the age of individuals too old to have been counted accurately by nascent census methods. However, most current epigenetic clocks underestimate the ages of older individuals (due to the well-known regression to the mean effect) and lead to relatively low age correlations in the oldest old.

Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on 7,039 blood and saliva samples from individuals older than 40, including 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105+), and 25 samples from supercentenarians (aged 110+). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (younger than 40) are correlated (r = 0.55) with age effects in old individuals (older than 90).

We further present a chromatin state analysis of age effects in centenarians. Our chromatin state analysis reveals that mean methylation of PRC2 target sites continue to increase late in life while exhibiting increased variability. Similarly, the mean methylation levels of two negatively age-related chromatin states (EnhA1, TxEx4) do not exhibit any leveling off effect late in life. These results suggest that one will be able to build accurate centenarian clocks for people who live beyond 120 years. The centenarian clocks are expected to be useful for validating claims surrounding exceptional old age.