The Influence of p53 on Aging is Far From Fully Understood

The p53 protein sits at the intersection of aging and cancer. Too much p53 activity and cell is activity is shut down, cells are made senescent more aggressively, and this leads to accelerated aging. Too little p53 activity, and precancerous cells might survive to form an ultimately fatal tumor. This is a considerable oversimplification of a very complex set of systems, however. There are plenty of exceptions to the above rule, including examples of conditional upregulation of p53 in mice that both extends life and reduces cancer incidence. The open access paper here discusses some of the complexities and contractions in what is known of the role of p53 - a gene that is well studied, but not yet comprehensively understood.

To accelerate aging, p53 induces apoptosis or cell cycle arrest as a prerequisite to cellular senescence; both can impair the mobilization of stem and progenitor cell populations. To suppress aging, p53 inhibits unregulated proliferation pathways that could lead to cellular senescence and a senescence-associated secretory phenotype (SASP), which creates a pro-inflammatory and degenerative tissue milieu. A review of mouse models supports both possibilities, highlighting the complexity of the p53 influence over organismal aging. These models were originally designed to study cancer but some appear to impact aging and longevity as well. They range from complete p53 null mutations to truncations or point mutations that alter activity. A comparison of these models reveals the complex influence p53 has over organismal aging - which can be independent or a consequence of its tumor suppressor role.

The initial mouse models were simple knockouts that produced no p53 protein. Most p53-/- embryos developed into apparently healthy adults, almost all of which succumb to cancer in about half a year. Heterozygous (p53+/-) mice develop cancer at a later age. Since simple p53-deletion increases cancer, simple overexpression should reduce cancer. Indeed, mice harboring an extra p53 gene contained within a BAC (bacterial artificial chromosome) had a lower incidence of cancer with no obvious effect on aging. Furthermore, increased gene dosage of p53 together with Arf lowered the cancer incidence and improved overall survival. ARF elevates p53 levels by inhibiting MDM2. Similarly, mice with a hypomorphic MDM2 allele, which increased p53 levels, showed a reduced cancer incidence without deleterious side effects. Thus, enhanced p53-mediated cancer suppression was not toxic to adult mice. It is possible that the pro-aging side effects of p53 are manifest only when p53 overwhelms the many regulatory mechanisms that modulate its activity.

The p53-null and p53-elevated mouse models support a simple notion of function; that is, p53 suppresses cancer without toxic side effects. However, other p53-altered mouse models confound this notion. p53 levels influenced aging in mice defective for BRCA1. BRCA1 repairs DNA double strand breaks (DSBs) created during DNA replication as a part of the homologous recombination repair pathway. Deleting one copy of p53 rescued brca1-/- mice from embryonic lethality but these mice displayed an early aging phenotype. Moreover, decreased capacity to repair DSBs caused p53-dependent early cellular senescence in cells and early organismal aging. Another genetic alteration that implicates p53 in aging is REGγ. REGγ-deficient mice display early aging. Elevated p53 might contribute to this phenotype because REGγ is a proteasome activator that regulates p53. Finally, skin-specific MDM2 deficiency resulted in p53-induced senescence in epidermal stem cells and precocious skin aging. These examples are interesting contrasts to the MDM2 hypomorphic allele described above, which reduced cancer without side effects, and suggests that different aspects of p53 regulation, coupled with genetic and environmental variances, can drive distinct biological outcomes.

Further complicating the picture, there are multiple p53 isoforms and family members (p63 and p73) generated from variant promoter usage, alternative splicing, and alternative translation initiation. How these isoforms differ functionally is not fully understood. There is evidence that some of these isoforms could influence aging. For example, expression of the N-terminally truncated p53 isoform in mice lowered cancer risk at the expense of early aging. These mice showed poor tissue regeneration, implicating a defect in stem and progenitor cells. Supporting this possibility, old p53+/- mice exhibited increased levels of hematopoietic stem and progenitor cells, but not if N-terminally truncated p53 was present. The truncated p53 likely forms a tetramer with full-length p53 to improve stability and nuclear localization. Another isoform stabilized p53 in the presence of MDM2. Thus, p53 isoforms have the potential to influence p53 function in a manner that affects aging.

Link: https://doi.org/10.21037/tcr.2016.12.02

Comments

My impression is that p53 is activating the cell repair cycle. And if there are adequate repair pathways the cell goes back to normal.

On The other hand if the repairs are not so profound or successful we have senecence promotion . Therefore, the senolytics inhibiting p53 kill the cells that are taking to long to repair. For robust improvements, we probably should be upregulating the p53 as a default mode but periodically shut it down to cleanup the SC build up...

. I am oversimplifying, of course, since each pathway might have multiple effects and functions. After all, there is no intelligent design. Only an evolutionary optimization.

What is remarkable that the mice with knockout p53 still managed to live to 6 months old and be relatively healthy. For a fast reproducing species there must be a strong evolutionary pressure to preserve the p53 partway, even if by 6 months old a mouse can have 4-5 generations of offsprings. Probably, the selection pressure was to survive the lean years where 6 months lifespan could eradicate the species...

Posted by: Cuberat at April 25th, 2019 5:52 AM

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