Certain p53 Sequence Changes are Indicative of Species Longevity

Scientists here expand upon prior research indicating that longer-lived species tend to exhibit certain types of sequence difference in the tumor suppressor gene p53 - a gene also involved in many other processes relevant to aging. One might compare this with past studies that examine the number of copies of this gene in long-lived, larger species. Elephants have many copies of p53, for example, which might go long way towards explaining why they don't exhibit higher cancer rates despite their great size, and thus greater number of cells.

The p53 protein is a well-known tumor suppressor and TP53 is the most often mutated gene in human cancers. On the cellular level, decreased p53 functionality is essential for cellular immortalization and neoplastic transformation. However, the role of variations in the p53 amino acid sequence on the organism level has not been studied systematically. Here, we presented an in-depth correlation analysis manifesting the dependencies between p53 variations and organismal lifespan to address the role of p53 in longevity. To date, p53 expression has been detected in all sequenced animals from unicellular Holozoans to vertebrates, with the lone exception of the immortal Turritopsis jellyfish.

The results from Protein Variation Effect Analyzer show that the variability in lifespan among closely related species correlates with specific p53 variations. Long-lived organisms are characterized by in-frame deletions, changes, insertions or specific substitutions in the p53 sequence. It is likely that the changes imposed on p53 in long-lived species enable p53 to interact with different multiple protein partners to induce gene expression programs varying from those induced in species with relatively normal lifespan.

We can anticipate that these gene expression programmes would enable following changes: 1. more efficient tissue repair through autophagy, 2. loss of senescence, 3. enhanced clearance of senescent cells by the immune system, 4. enhanced regulation of intracellular reactive oxygen species (ROS) levels 5. improved resistance of mitochondria to ROS-induced damage or 6. loss of immune senescence that occurs in humans with age. All of the mentioned processes have been previously described as significantly contributing to longevity. Thus, long-lived organisms apparently have a different mechanism of protection against cancer and their lifespan is not limited by somatic cell senescence caused by active p53 protein, which is the case for other species with shorter lifespan as mentioned above.

We inspected TP53 gene sequences in individual species of phylogenetically related organisms that show different aging patterns. We discovered novel correlations between specific amino acid variations in p53 and lifespan across different animal species. In particular, we found that species with extended lifespan have characteristic amino acid substitutions mainly in the p53 DNA binding domain that change its function. These findings lead us to propose a theory of longevity based on alterations in TP53 that might be responsible for determining extended organismal lifespan.

Link: https://doi.org/10.1101/2020.05.06.080200


Can a genetically modified mouse with many copies of p53 be compared against the controls?

Posted by: Cuberat at May 21st, 2020 8:08 AM

Hi there! Just a 2 cents.

There has been ambuiguity about tumor suppressor genes like p53, where sometimes they are/may be beneficial and could have a sort of survival signal (à la hormesis), where in mild dose they would do extension of lifespan like hormesis does. The benefit is protection from cancer/tumor suppressing - at higher doses of ROS (because cancers Already use ROS as important element to strive; but not Ultra-High levels of it, only high-levels of it; because ultra-high levels terminate the cancer cells from excess ROS; such as in radiation and chemotherapy against cancer; where the whole purpose is to create extreme ROS to kill cancer; cancer mostly strive on high-ROS dose, over that they die or cell turn senescent); p53 activates p21 after which its transcription creates replicative senescence. In cancer, it's different it is oncosenescence and different than replicative senescence. There it is more p53-p16 axis. While replicative senescence is p53-p21 axis.

Animals like elephants that have extra copies of p53 are protected from cancer; but it's a double-edged sword; certain tumor suppressors are very much contributors to replicative senescence itself; you can see ROS signal elevate as p21 shows up. It is why an elephant will live 70-90 years not 200...when I transpose this on a bowhead whale (living over 200 years) that probably also has more copies of p53 and never gets cancer...then it means that tumor suppressors can be 'more copies' as long as they are kept 'off'...for a long while. Whenever they are needed, then they will stop cancer - but then, they have to Disappear/remain quiescent again; because they themselves contribute to acceleration of aging (via accelerated telomere shortening) by elevation of mitochondrial and nuclear (NOX NADPH oxidases) ROS emissions). So this mean more tumor suppressors - but less need of them (because all is maintained cancer-free/damage-free) and, if, needed, then they do the job and its back to normal quick. So it's a 'hit-and-run' approach, get all the tumor suppressors and stop the cancer immediately...and immediately go back to no tumor suppressor expression. Doesn't mean there are no copies, there are more copies - just more them - silent. And, only, called, if needed should there ever be a cancer forming. The systems would not be overused/remain for the most part quiescent, because low-to-no damage in these long-live animals; they don't develop cancer -because no damage...so then why all these extra-copies? an Extra to make sure that any possible cancer is immediately neutralized; but, once it is, these mechanisms disappear and do not interefer with the aging process (and even cause it by the elevating ROS they contribute to the moment they show up); like they do in short lived animals.
Chemotherapy can save a life (it did not save my mother's life...it, in part, killed her; her cancer did, but so did the chemo), chemotherapy and radiation cause an Extreme amount of telomere damage; and its why a person can age 5-10x faster when they are on chemo (one burst of chemo equals 500-3000pds/y lost; which equals aging by 20-60 years extra 'overnight'); the need to destroy the cancer is primordial but the cancer will never make someone perish faster then radiation/chemo because the telomeres uncapp at an extreme speed as accumulate an inordiante amount of damage/foci (meaning extreme DDR activation = massive senescence). The metastasis of the tumor can be faster/slower depending on its malignancy; but the chemo could hasten things. In the future there must be 'targeted' delivery to cancer cells only. Whole Body Telomerase Interdiction (WILT) is a solution...but there is better...for example, you do not want to lose telomerase, it's extremely important to not lose it; when cancer hijacked telomerase...then..you have to methylate telomerase gene in the cancer's genomic regions/in DNA methyl clock; while demethylating the gene in the healthy cells. Astragalus is one herb that does this, it is capable of activating telomerase (in healthy cells, only) and deactivating telomerase (in cancer cells, only). And it does this by targetting methylating of TERT genes locust (in CpG islands/silence it) in genome for the unhealthy rogue cells; while it demethylate it in the regions for healthy cells (unsilence it). That is what allows up to keep telomerase (for preserving our telomeres long enough (...to matter), and slow down the shriking rate), while Accelerating the shortening rate in cancer cells and depriving them of telomerase/ALT/recombination; so that they senesce.

Studies showed that fibroblast that have the most replicative bouts (such human BJ fibroblasts) push back the arrival of the tumor suppressors the latest possible; the instant they show up, senescence comes soon enough. *mmortalized fibroblast do not accumulate any tumor suppressors/they are nill/negative for them (and why they can be so/*mmortalized). Tumor suppressors (to destroy tumor) work by ROS mechanism 'fight fire with fire' (it is better with water).

Just a 2 cents.

PS: My guess is that a mouse with more p53 copies would be more protected of cancer, like elepphant, and its life would not be 'that' changed that much; so it could live an overall same life cancer free;;but maybe a lil be shortened because p53 (ROS) affects heatlhy cells too during the 'attempt to destroy the tumor' by immune system calling p53/p16/TNF-a/INF-g..etc. In the end, the mouse's levels of tumor suppressor (p21 for replicative hayflick limit as its telomere would reach the 'low' ~37kbp height (for a mouse tall telomere) = replicative signal by telomere foci DDR) would rise dramatically - at the end of its life, like it does right now too. So it would not change much in the end; only better cancer protection. Elephants live 90 years, even so of having more copies of p53/tumors suppressors (so no cancer)...but they still accumulate telomere foci damage and have DDR/arrival of p21 tumor suppressors to 'enter replicative senescence' at that late-age point too.

Posted by: CANanonymity at May 22nd, 2020 1:26 AM
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