David Sinclair (by way of Shinya_Yamanaka) research on reversing aging:

[JohnBoy2000]

Something similar to stem-cell therapy, gene therapy:



Basically contending it's possible to "scrub off" epigenetic faults that produce age complaints.

Clean "stained" DNA.

As I understand it's further the work of Nobel Prize winner:

Shinya Yamanaka - Wikipedia

en.wikipedia.org

I need this to get approval ASAP before I become "that guy at the bar".

 

[ecstacylover]

For anyone interested, Yamanaka showed that somatic cells could be dedifferentiated by a combination of 4 transcription factors, essentially resetting their epigenetic clock to 0 in the process.

More results are showing that transient exposure to the so-called Yamanaka factors can rewind the epigenetic clock while maintaining somatic identity. Take this paper from last year, which drastically rejuvenated (i.e. by decades) the epigenome and transcriptome of middle-aged human fibroblasts via transient exposure to the Yamanaka factors. As a result, their functional attributes (e.g. collagen production) were restored to youthful levels. There's also 2 recent in-vivo mouse studies showing similar results.

Obviously the efficiency of rejuvenation would have to be improved and the cancer risk reduced, but it's still super exciting results. Probably it will be first used as disease-specific therapy (a la the Sinclair results in regard to glaucoma), but at least we can dream of more general application down the road.

Oh check out the heterochronic parabiosis experiments as well. The circulating factors in young animals (and/or dilution of the circulating factors in older animals) are sufficient to observe rejuvenation in older animals, which suggests that aging is a state which is, at least in part, being actively maintained. Obviously the irreversible loss of genetic information is contributing as well, but that probably not the main driver of aging (at least on timescales of human lifetimes).

 

[JohnBoy2000]

The researcher mentions a current treatment called NMN, which apparently caused some anti-aging benefits:



Nicotinamide mononucleotide.

I used topically a skin care product containing nicotinamide a month ago and it gave me horrid side effects.

It's definitely not the stem-cell related therapy in question, but I found it interesting he mentioned it in this lecture.

 

[JohnBoy2000]

There's an endocrinologist called "Mark Gordon" who appeared on the JRE a couple times, advocating for TRT as a counter measure to aging.

I don't think that really panned out.

.........

Getting older sucks.

 

[Jabberwocky]

It's interesting that the chemicals produced by senescent cells called SASP, actually make non-senescent cells senescent. If the cytokines secreted by SASP cells can affect epigenetics to the point that it induces senescence in otherwise viable cells, it's not unexpected the reverse is true; namely that some process could reverse epigenetic changes in senescent cells and revert them to viability.

Personally, suppression of MTOR c1 signaling (and associated pathways) by consumption of herbal products (fisetin, quercetin, oleocanthal, etc.) and weekly extended fasting (48-120 hours), has helped arrest my multiple sclerosis. This is likely due to induction of profound autophagy in the brain and thereby allowing for normal remyelination.

The cytokines cascade caused by (likely genetic/epigenetic) chronic MTOR C1/NLRP3 inflammosome activation, which includes: IL-1B, IL-6, IL-17/17A, IL-23 actually causes chronic microglial inflammatory activation and prevents autophagy in the brain which prevents the correct remyelination of sclerosis caused by MS. It is also now known that IL-17 /17a is causative with respect to MS, due to activation of Th17 inflammatory cells.

Of interest is that postmortem evaluation of the brain's of people suffering from MS identified that the cells had significantly shorter telomeres and were therefore cellularly older than expected. The same is true for cells in brains of people affected by SARS COVID-19. Researchers believe that this is due to inflammatory based epigenetic changes caused by activation of MTOR C1 and the NLRP3 inflammosome.

OF NOTE: most senolytics including fisetin, quercetin, rapamycin, etc inhibit the MTOR C1 signaling pathway as well as the NLRP3 inflammosome.

 

[ecstacylover]

The researcher mentions a current treatment called NMN, which apparently caused some anti-aging benefits:

I take 800mg oral NMN daily, although I know of one rodent study suggesting that both NR and NMN poorly distribute to tissue prior to nicotinamide conversion (this slightly improves with IV administration). One reason why this matters, sirtuin deacylases (one of the things you're trying to activate with NR/NMN) are actually inhibited by nicotinamide. Apparently some groups have also had difficulty replicating its ability to increase rodent lifespan. Anecdotally, NMN does seem to make my vision crisper, and provides a clean mental energy throughout the day.

Probably the intervention with the most consistent evidence is rapamycin, which reliably increases rodent lifespan across strains, at different points throughout development, and with different dosing schedules. The increased lifespan in wild-type is often >10%, and even up to a 25% increase.

Personally I was opposed to starting it because I presumed it would antagonize skeletal muscle growth and/or maintenance, but apparently it actually preserves muscle function in aged rodents. Also, there's a prominent aging researcher who claims to know more than a handful of people who have actually gained lean muscle mass on rapamycin. I'm probably going to wait about 6-9 months as I'd like to put on an additional 10lbs of lean muscle, but after that I'm going to start taking it.

It's interesting that the chemicals produced by senescent cells called SASP, actually make non-senescent cells senescent. If the cytokines secreted by SASP cells can affect epigenetics to the point that it induces senescence in otherwise viable cells, it's not unexpected the reverse is true; namely that some process could reverse epigenetic changes in senescent cells and revert them to viability.

Personally, suppression of MTOR c1 signaling (and associated pathways) by consumption of herbal products (fisetin, quercetin, oleocanthal, etc.) and weekly extended fasting (48-120 hours), has helped arrest my multiple sclerosis. This is likely due to induction of profound autophagy in the brain and thereby allowing for normal remyelination.

Have you heard of FOXO4-DRI? It's a peptide but there's evidence that it selectively induces apoptosis in senescent cells, but I guess the issue is how do you monitor whether it's actually working? There's a few anecdotal reports of people taking it, but it's hella expensive.

That makes sense that it's helping though. I imagine the debris would otherwise be triggering the immune system even more.

 

[Skorpio]

I take 800mg oral NMN daily, although I know of one rodent study suggesting that both NR and NMN poorly distribute to tissue prior to nicotinamide conversion (this slightly improves with IV administration). One reason why this matters, sirtuin deacylases (one of the things you're trying to activate with NR/NMN) are actually inhibited by nicotinamide. Apparently some groups have also had difficulty replicating its ability to increase rodent lifespan. Anecdotally, NMN does seem to make my vision crisper, and provides a clean mental energy throughout the day.

Probably the intervention with the most consistent evidence is rapamycin, which reliably increases rodent lifespan across strains, at different points throughout development, and with different dosing schedules. The increased lifespan in wild-type is often >10%, and even up to a 25% increase.

Personally I was opposed to starting it because I presumed it would antagonize skeletal muscle growth and/or maintenance, but apparently it actually preserves muscle function in aged rodents. Also, there's a prominent aging researcher who claims to know more than a handful of people who have actually gained lean muscle mass on rapamycin. I'm probably going to wait about 6-9 months as I'd like to put on an additional 10lbs of lean muscle, but after that I'm going to start taking it.


Have you heard of FOXO4-DRI? It's a peptide but there's evidence that it selectively induces apoptosis in senescent cells, but I guess the issue is how do you monitor whether it's actually working? There's a few anecdotal reports of people taking it, but it's hella expensive.

That makes sense that it's helping though. I imagine the debris would otherwise be triggering the immune system even more.

I would be very wary of anything that inhibits p53's apoptotic potential. p53 is by far the most important tumor suppressor , and its inactivation occurs in 50% of cancers.

 

[ecstacylover]

I would be very wary of anything that inhibits p53's apoptotic potential. p53 is by far the most important tumor suppressor , and its inactivation occurs in 50% of cancers.

Were you referring to the FOXO4-DRI? That one disinhibits p53, but supposedly only within senescent cells.

 

[Skorpio]

Were you referring to the FOXO4-DRI? That one disinhibits p53, but supposedly only within senescent cells.

Egads, serves me right for reading articles at a late hour. Seems like an interesting senolytic.