Slower DNA Damage Accumulation in Immune Cells Correlates with Species Life Span

Today's open access research is an assessment of DNA damage accumulation in a variety of species, showing the pace of mutational damage correlates with species life span, at least as assessed here in immune cells from blood samples, and using a marker that identifies the response to short telomeres as well as forms of DNA damage. The DNA of the cell nucleus, the genetic blueprint for near all of the proteins produced in a cell, accumulates damage over time due to the normal haphazard chemical reactions that take place constantly inside cells. These mutational changes are largely irrelevant to cellular operation, but some can cause disruption in metabolism, or, worse, make a cell cancerous, by causing certain proteins to be produced in a broken or altered state. Near all mutational damage to DNA is quickly repaired by the highly efficient array of DNA repair mechanisms that a cell is equipped with. But some inevitably slips past.

The way in which mutation leads to cancer is fairly straightforward, but it is less obvious as to how random mutation in single cells can contribute meaningfully to other aspects of aging, such as widespread tissue dysfunction. The present consensus is that the important mutations are those that occur in stem cells and progenitor cells, able to spread widely throughout a tissue via the replication of daughter somatic cells created by those stem cells and progenitor cells. It was also recently suggested that DNA damage, even when repaired, and more or less regardless of what is damaged in DNA, leads to epigenetic changes characteristic of aging, and these epigenetic changes are what causes cell function to decline. In this view, a larger amount of unrepaired DNA damage, the marker usually measured, is indicative of the true cause of harm, which is more frequent DNA repair and thus epigenetic change.

The authors here are primarily focused on DNA damage markers that occur due to critically short telomeres in additional to mutational damage. Average telomere length in tissues, and the fraction of cells with critically short telomeres, is most likely downstream of stem cell function. Telomeres shorten inexorably with each cell division in somatic cells, and cells eventually self-destruct, or become senescent and are destroyed by the immune system. Stem cells use telomerase to maintain long telomeres, and deliver daughter somatic cells with long telomeres into tissues to make up the losses. So telomere length in tissues is a function of how rapidly cells divide and how frequently replacement cells are delivered by the supporting stem cell population - the pace of the latter is well known to decline with age.

Slower rates of accumulation of DNA damage in leukocytes correlate with longer lifespans across several species of birds and mammals

Different species have very different lifespans ranging from less than 1 day for mayflies to more than 400 years for the Greenland shark. However, the exact cause of these differences in longevity are still largely unknown. Our group recently showed that the rate of telomere shortening with age correlates with lifespan in a variety of species from birds to mammals. Species with very fast telomere shortening rates such as mice have very short lifespans, and species with very slow telomere shortening rates such as humans have very long lifespans. It is interesting to note that species that share a similar longevity in spite of being evolutionarily distant like flamingos and elephants, also show a similar rate of telomere shortening, while evolutionarily closer species like mice and elephants, show very different longevities and also have very different rates of telomere shortening.

These findings suggest that longevity can be determined, at least in part, by epigenetic traits, such as the rate of telomere shortening. Furthermore, these findings pose the interesting question of which is the molecular determinant by which higher telomere shortening rates lead to shorter longevities. An obvious answer is that higher rates of telomere shortening will be associated to faster accumulation of critically short/dysfunctional telomeres, which are known to contribute to activation of a persistent DNA damage response stemming from telomeres, which leads to loss of cell viability and aging phenotypes. Thus, species that shorten telomeres at faster rates will reach telomere exhaustion and trigger a persistent DNA damage response earlier than those species that are able to maintain telomeres protected for a longer period of time. A short/dysfunctional telomere is recognized by the cell as an irreparable DNA double strand break (DSB), triggering a persistent DNA damage response which results in phosphorylation of γH2AX, and which eventually leads to cell death and/or senescence. In turn, induction of cellular senescence either owing to critically short telomeres or to other insults is also associated with increased γH2AX levels, involving in some instances the mTOR pathway. Thus, accumulation of cells with DNA damage throughout lifespan should also correlate with species longevity.

Here, we find that increased global rates of DNA damage, as determined by the DNA damage marker γH2AX which detects occurrence of double stranded DNA breaks in the genome, inversely correlates with species longevity. In particular, we determined here the rates of increase of the DNA damage marker γH2AX in leukocytes of phylogenetically distant species of birds and mammals in parallel and using the same experimental method. Previous studies have also shown a correlation between certain types of DNA damage and aging. Indeed, DNA damage accumulation with aging and telomere shortening may be related processes. Critically short telomeres as the result of cell proliferation throughout life to repair damaged tissues trigger a DNA damage signal specifically at telomeres.

We also measured the percentage of short telomeres of the species in this study, and we found that all of the species showed an increase in the percentage of short telomeres with age. This result is concomitant with the fact that average telomere length shortens with age in many species. Several studies have suggested that the percentage of short telomeres is more indicative of health and senescence than average telomere length. The percentage of short telomeres is an important metric since it is the length of the shortest telomere in a cell that induces a DNA damage response and cell senescence rather than the average telomere length of the telomeres on all of the chromosomes. Here we also noticed a mild trend for species with longer maximum lifespans to have a lower rate of increase of percent short telomeres, thus accumulating short telomeres more slowly with age. We also observed that species with the highest rates of γH2AX increase have the highest rates of increase of percent short telomeres with age. These results make a connection between γH2AX DNA damage, short telomeres, and lifespan. As cells accumulate DNA damage and short telomeres, they will enter into a state of senescence, thus accelerating the aging process and shortening lifespan.

Comments

Im a transplant survivor and used the immunosuppressant Ciclosporin A which reduced white leucocyte levels. I suppose that could or will reduce my health/lifespan?

Posted by: thomas.a at November 26th, 2019 4:19 PM

Hi Thomas, Just a 2 cents. I share your grief and empathizing (I'm atherosclerosis survivor).

It is possible. If it did reduce leukocytes count it will affect your immunity (immunosenescence; which can cause cancer formation because immune system too impaired); leukocytes count that are reduced are seen in people with compromised immune system; the person having this continuously is at risk (because the mortality rises/people have died within certain years from having these low wbc counts and having an impaired immune system for this long; it allows invaders/deleterious mutation to form (rogue cancer cells hijacking your body because undetected and unremoved)). It is understandable to lower immune system to avoid 'auto-immunity' problems with transplant/body rejects it/or attacks it(self). My maternal grand-mother died of autoimmunity disease (lupus); while my mother (daughter of grand-ma), died of, cancer (both at same age, 55 and 56 years old; my mom was telling me that she was afraid of dying smae thing as her mother when she had jaundice that set the whole thing up and then foudn out she had pancreatic cancer, and later, it became stomach cancer); and it kind of happened....but it is different, mother was lack of immunity (cancer strives); awhile grand-ma was auto-immunity attack))). So, yes, I know I'm not the only one here on this website where the family has been devastated and hope we find cures/SENS therapies soon, because we are/our family was sick and we have their genetic (in other words...we are not blessed (in life) let's say/unlucky)). The main point is get back your immune system in shape, as quick as you can; the longer this lasts the worse/faster the outcome you do not wish, later down the road. Immunity maintenance is crucial for longevity (otherwise your thymus would involute faster...and immune system won't be able to defend you against any invasion)). A supercentenarian woman had small telomeres in her leukocytes, but tehy were intact and she lived to 115 years old`as such immunity was crucial to her reaching that age (when many elders die of cancer or pathgoen diseases (pnemonia, ...); they could reach her age but without immunity there; it's quasi impossible (because at that age your immune system is weakened and can't fight off the invaders as well anymore; so it's bound to become dysfinctional (and once, no more immunity, it can be death very soon)). As seen, in elders having 'short bouts' of viral/pathogen disease/or cancer, and then dying rapidly in few motnhs or few weeks; it's hard to 'defend' body if no more immunity.

Good Luck and Continue Getting Better,

Just a 2 cents.
.

Posted by: CANanonymity at November 27th, 2019 12:26 AM

I found out of Lupus few years ago and thought it might indirectly benefit immune research in transplantation. I donated to Lupus Foundation. I would mostly like to donate only to SRF but since I might need a new organ in the future I donate to Solving Organ Shortage (SOS), Organ Preservation Alliance (OPA), New Organ (NO), Cryoprize and Multidisciplinary Association for Psychedelic Studies (MAPS), because Im out of work because of trauma. Im on social welfare and donates 50.000 NOK every year which is nearly 1/4 of income. I donate only 100-1000 NOK to SRF. Thats I think is one of the major problems with aging research. People say there are other problems that should be solved first. This will change under the silver tsunami. But I think if other problems were solved people would have more focus on aging. I will participate inn LLP fusion investments on Wefunder because when we have fusion we will have clean water to all, we already have Carbon Nanotubes (CNT), we only need electricity to pump the water. Many other problems will be solved with energy tech.

Posted by: thomas.a at November 27th, 2019 7:07 AM

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