Linking up the theories of aging

Research reports continue to appear that identify linkages between theories of aging I have covered in the treatise Anti-Aging Firewalls – The Science And Technology Of Longevity.  The latest shows a link between the Telomere shortening and damage, the Programmed epigenomic changes, the Susceptibility to cancers and the Decline in adult stem cell differentiation theories.  The common element is epigenetic modification in the Ink4a-Arf locus.  These genes encode the proteins P16(Ink4a) and P19(Arf) which prevent inactivation of the tumor suppressor RB, and P19ARF, which stabilizes the tumor suppressor P53.    

According to the Telomere shortening and damage theory, when telomeres in somatic cells become too short as a result of successive cell divisions the cell is likely to go into a state of cell senescence where it can no longer divide and does not die. Senescent cells tend to strongly express the anti-cancer genes P16(INK4a) and P19(Arf).   So, these genes offer senescent cells an alternative to becoming malignant.  But senescent cells are likely to become bad neighbors sending out signals that can lead to organ dysfunction or degeneration.  Further, in discussing the Programmed epigenomic changes theory,   I mentioned how p16(INK4a) tends to be increasingly expressed with age and how it tends to inhibit the differentiation of adult stem and progenitor cells.  Thus, P16(INK 4a) plays a central role in the Decline in adult stem cell differentiation theory.  Also, it “induces an age-dependent decline in islet regenerative potential(ref).” Increasing expression of P16(INK4a) with age therefore tends to compromise organ repair and regeneration. P16(INK4a) provides a central defense against cancer in the case of senescent cells and is therefore important in the Susceptibility to cancers theory of aging.  

There is another side to cell senescence, however:   “Senescent cells, particularly senescent stromal fibroblasts, secrete factors that can disrupt tissue architecture and/or stimulate neighboring cells to proliferate. We suggest that senescent cells can create a tissue environment that synergizes with oncogenic mutations to promote the progression of age-related cancers(ref).”  I have mentioned the paradoxical role of P16(INK4a) in the Blog post Dr. Jekyll and-Mister Hyde Proteins. The new research, reported in a publication entitled Polycomb Mediated Epigenetic Silencing and Replication Timing at the INK4a/ARF Locus during Senescence provides a new link between the theories and hints at anti-aging intervention that can address all of these theories. 

The language of the publication like the title is highly technical, so I attempt a simplified explanation of the basic findings here.  Basically, in young cells, Polycomb group proteins act on the INK4/ARF gene regulatory domain so as to the keep the expression of P16(INK4a) turned off, the gene is silenced.  In senescent cells, however, there are epigenetic modifications (DNA and histone methylation changes) which block the inhibitory actions of the polycomb group proteins, so the P16(INK4a) and Arf genes are activated.  So, cell senescence leads to another pro-aging effect, the activation of the P16(INK4a) and Arf genes. Earlier, in the Anti-Aging Firewalls treatise I identified the increasing expression of P16(INK4a) with aging as a biomarker of aging and possible cause of age-related changes.  In fact, I identified this as possibly one of the major aging mechanisms according to the Programmed epigenomic changes theory.  At that time, however, I had no notion of how possibly to slow or halt the accumulation of INK4/ARF with age. 

The new results suggest two possible routes of intervention.  The first is to slow or stop cell senescence, something I am already attempting to do.  Since too-short telomeres is the primary cause of such senescence, according to the new research telomerase activation may address both the cell senescence and the accumulation of P16(INK4a) issues.  Personally, I am increasing my daily dose of Astragaloside IV to the 100mg a day provided in the new version of the Astral Fruit supplement. 

A second kind of possible anti-aging intervention with respect to slowing buildup of P16(Ink4a) with age comes to my mind as well.  It is to halt or block the cell and histone demethylation and deactylation patterns associated with cell senescence, specifically the histone deactylation patterns in senescent cells that are associated with blocking the inhibitory actions of Polycomb  proteins on expression of P16(Ink4a).  The molecular biology involved in this particular instance is quite complex(ref).  But it could be that histone deactylase promoters could be useful to limit the expression of P16(Ink4a).  See the recent blog post Histone acetylase and deacetylase inhibitors.  This is a speculation on my part but there could be something to it.