Supercentenarians’ Extreme Longevity Attributed to DNA Repair, New Study of 105-Year-Olds Finds

Although researchers have found that only about 20% of our longevity can be attributed to genetics — with the rest credited to lifestyle and environmental factors — that one-fifth portion of the pie can still play a massive role in influencing both our lifespans and healthspans. While the population of healthy centenarians is growing every year, the global group of semi-supercentenarians (those living to age 105) and supercentenarians (those aged 110 years or older) is still a relatively small pool. 

To better understand what helps these adults live longer than most, a research team based out of Italy and Switzerland performed extensive genetic analysis from an area in the world that is rife with semi-supercentenarians and supercentenarians — the Italian peninsula. From detailing the genomes (the complete set of genes and genetic material that someone carries) of these 105-and-up adults and comparing them to healthy younger counterparts, Garagnani and colleagues uncover several genetic differences in these extreme agers, specifically with genes heavily involved in DNA repair and healthy cell functioning. 

With this study’s results, the genomic makeups and genetic mutations — or lack thereof — of semi- and supercentenarians add to the evidence that maintaining proper DNA repair mechanisms with age may be a crucial component of reaching extreme longevity. As stated by one of the study’s authors, Professor Massimo Delldeonne, "This study constitutes the first whole-genome sequencing of extreme longevity at high coverage that allowed us to look at both inherited and naturally occurring genetic changes in older people."

How DNA Damage Ages Us 

Damage to our DNA is inevitable, as our cells constantly get exposed to harmful compounds that can lead to mutations, misfolded proteins, and dysfunction in our mitochondria — the energy factories of our cells. While our cells can typically work efficiently to repair these bits of broken DNA, this ability deteriorates as we grow older.

DNA damage can occur from both outside sources — like excess sunlight on our unprotected skin, polluted air, or pesticide-laden food — and from sources inside our body, like an imbalance of inflammatory compounds called reactive oxygen species (ROS). The combination of an abundance of ROS with low levels of antioxidants to neutralize the reactive compounds leads to oxidative stress, causing damage to our cells and DNA. 

With age, mutations in genes involved with DNA repair are more likely to take place, causing these repair processes to become more error-prone. As time goes by, more and more DNA damage accumulates without getting fixed, leading to accelerated aging and organ dysfunction. With that in mind, Garagnani and colleagues aimed to uncover whether adults living to 105 and beyond have a unique genetic makeup that allows for their DNA to maintain its repair mechanisms longer than most — and, it turns out that they do. 

Detailing the Genetic Distinctions of Supercentenarians

As previous research has found that younger siblings of semi-supercentenarians are 35 times more likely to reach age 105 than the general population, it’s clear that there is a genetic component involved in extreme longevity. Not only do these people live longer, but they also largely avoid many or all of the common age-related diseases like heart disease — our current leading global killer. In light of this, Garagnani and colleagues speculated that these healthy 105- to 110-year-olds would have unique variations in their gene activity and sequence that protected them from these common age-related diseases.

In this study, the research team used a process called whole-genome sequencing to analyze the complete sets of genes and genetic material in 81 Italian adults with an average age of 106, comparing them to 36 healthy adults in their late 60s that lived in the same area. To verify their data, Garagnani and colleagues cross-referenced this genome sequencing with a recent study that compared the genomes of 333 Italian centenarians (age 100 and above) with 358 healthy younger people who lived in the same area. 

Dynamic DNA Repair Reaps the Reward of Longer Lifespan

After performing this comprehensive analysis, the researchers uncovered several genetic changes that were more common in the 105+ group than the healthy younger adults, specifically between three genes. These gene variants were also found to be replicated in the second study dataset of Italian centenarians.

The most significant associations were found with a gene called STK17A, which had increased activity in the heart, lungs, nerves, and thyroid of the supercentenarians. This gene is highly involved in our body’s response to DNA damage, allowing for efficient repair to take place. STK17A also plays a role in reducing ROS levels and oxidative stress, as well as regulating apoptosis — programmed cell death that can remove damaged or dysfunctional cells. As STK17A activity was the most prominent genetic difference between the younger and older adults, the researchers support the notion that DNA repair mechanisms and regulating oxidative stress play a central role in reaching extreme longevity.

Two other genes that had different activity between the groups were COA1 and BLVRA. Although important for mitochondrial function and promoting cross-talk between our cell’s mitochondria and nucleus, COA1 activity was actually reduced in the semi- and supercentenarians. This reduction may be beneficial for long-term health, as other research has found that high COA1 activity may promote colorectal cancer, leading some researchers to label it an oncogene — a gene that can transform a normal cell into a tumor cell. Thirdly, increased activity on the BLVRA gene was found in the 105-110+ adults, which is a gene that modulates aging by regulating programmed cell death and eliminating ROS buildup in the cells. 

Lastly, the research team looked at how many somatic mutations — changes to the DNA sequence that won’t get passed along hereditarily but can impact aging and disease — occurred in various genes between the two age groups. It would be expected that the adults living four decades longer would have more mutations accumulated over the years, due to longer exposure to DNA-altering events, but the opposite was true — the semi- and supercentenarians had fewer mutations in six of the seven tested genes. These differences may play a role in the older adults’ protection against heart disease — not because they carry specific genes that lower cardiovascular risk, but because of their resistance to somatic mutations with age.

Will Better DNA Repair Lead to Extreme Longevity? 

This study reveals several genetic clues related to the unsolved mystery of why certain populations are more likely to reach extreme longevity. Although modifying our genes to be more supercentenarian-like is not a viable option — yet — some research has found that we can boost our body’s ability to repair DNA more effectively with certain compounds, including NMN (nicotinamide mononucleotide), a precursor to the vital coenzyme NAD+. However, this preliminary research has not yet been replicated in humans, so we don’t know for sure if NMN can boost our DNA repair — or extend lifespan to supercentenarian status. 

For now, this study provides an important step in learning more about how and why some people easily reach the century mark without developing life-shortening diseases along the way. As concluded by senior author Professor Claudio Franceschi, "Our results suggest that DNA repair mechanisms and a low burden of mutations in specific genes are two central mechanisms that have protected people who have reached extreme longevity from age-related diseases."

References: 

Garagnani P, Marquis J, Delledonne M, et al. Whole-genome sequencing analysis of semi-supercentenarians. Elife. 2021;10:e57849. Published 2021 May 4. doi:10.7554/eLife.57849

Giuliani C, Sazzini M, Pirazzini C, et al. Impact of demography and population dynamics on the genetic architecture of human longevity. Aging (Albany NY). 2018;10(8):1947-1963. doi:10.18632/aging.101515

Sebastiani P, Nussbaum L, Andersen SL, Black MJ, Perls TT. Increasing Sibling Relative Risk of Survival to Older and Older Ages and the Importance of Precise Definitions of "Aging," "Life Span," and "Longevity.” J Gerontol A Biol Sci Med Sci. 2016;71(3):340-346. doi:10.1093/gerona/glv020

Wilk A, Hayat F, Cunningham R, et al. Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. Sci Rep. 2020;10(1):651. Published 2020 Jan 20. doi:10.1038/s41598-020-57506-9

Xue Y, Li PD, Tang XM, et al. Cytochrome C Oxidase Assembly Factor 1 Homolog Predicts Poor Prognosis and Promotes Cell Proliferation in Colorectal Cancer by Regulating PI3K/AKT Signaling. Onco Targets Ther. 2020;13:11505-11516. Published 2020 Nov 10. doi:10.2147/OTT.S279024