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Centenarians and Supercentenarians – It’s All in the Genes

Living longer is a far cry from aging well. Not many of us would want to live for an extensive time after our quality of life had significantly deteriorated, yet as a species we are surviving to much greater ages than our ancestors. A few people manage to achieve the best possible outcome, a very long and healthy life.

Of course, much can be explained away in terms of access to good nutrition, healthcare and educating ourselves against life shortening toxins such as smoking, but not all longevity can be attributed to environmental conditioning.

Sprightly older man
Sprightly older man

I’m sure we’ve all got that one relative who has done all the things you shouldn’t do; eaten junk foods, avoided healthy fruits and veggies, smoked and drank to excess and still barely has a grey hair on their head to betray their ripe old age, but what is it that singles out these miraculous die-hards from the rest of us?

It turns out that there is an unusual gene variant that gives these old-timers a superpower over their mental faculties.

Associate Professor of Pathology and Laboratory Medicine at Weill Cornell Medicine, Dr Jihye Paik and her colleagues, identified this rare gene in studies on humans who live beyond one hundred years. The variant has a catchy acronym of FOXO3 or Foxhead Box Protein O3. Her study follows on from an earlier one conducted on mice that showed agitated and stressed rodents rarely, if ever, possessed the FOXO3 gene. Those ultra-stressed mice developed an accelerated form of brain cell death.

The team then set about finding the variant in humans, which they did in January of this year. Further research suggested that the gene acts like a switch inside certain brain cells. We have a finite number of brain stem cells available to us from birth. These stem cells are like a blank canvas, waiting for a signal to tell them which type of cell to grow into, allowing us to make new memories, reinforce old ones or repair tissues that have been exposed to a build up of toxins from our everyday activities.

DNA and marker chemicals
DNA and marker chemicals

When old cells are worn out, a biochemical reaction triggers a stem cell to develop into a replacement. The problem is that since we are leading more and more stressful lives, which can result in more of those metabolic toxins to build up in our tissues causing damage, those stem cells can easily run short.

For those lucky few who possess the FOXO3 variant gene, the cell differentiation process is temporarily switched off until the stress levels begin to subside. That way, new tissues are formed from the stem cells at a time when they are most likely to survive. Dr Paik says; ‘If stem cells divide without control, they get depleted. The FOXO3 gene appears to do its job by stopping the stem cells from dividing until after the stress has passed.”

Her team found that when certain chemical markers are present, the protein enter the nucleus and tampers with the biochemical cascades associated with stress, tricking the stem cell into thinking it’s under viral attack. The result is that the cell lies dormant instead of developing into a new brain cell. Only after the inflammatory chemicals subside, can the process be reversed.

Paik and her team suggest that this regulatory power exhibited by the FOXO3 variants could explain why some forms of the gene are linked to extraordinarily long and healthy lives since they help to conserve brain stem cells into old age. There is, however, a potential drawback to this system. While dormancy can preserve our supply of stem cells for longer, we wouldn’t want its temporary effects to be extended. Even healthy brains need to create new memories and reinforce old pathways.

Dr Paik and her team plan to continue this research and hope to isolate any specific benefits to long term brain health that could be applied elsewhere. She also makes reference to the fact that initial indications suggest a link between regular exercise and a boost in FOXO3 efficacy, although she warns that it’s too early to make any proven correlations to longevity.

I am both gladdened and worried by this latest study, since FOXO3 could become yet another weapon in the arsenal of unethical companies offering designer babies to competitive parents. In a future where embryos are routinely screened for potential disease, could they also slip in an option for genes associated with extreme long life and stress resistance? None of us can answer that, but the potential for abuse grows daily.

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