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Comment by dist-epoch | Hacker News Reader

As in all things biology, that's not necessarily a good thing, otherwise we would have evolved it already. Surely there are downsides (cancer, ...)

> it has been suggested that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would be more susceptible to becoming cancerous if cell division continued. As such, it is becoming apparent that senescent cells undergo conversion to an immunologic phenotype that enables them to be eliminated by the immune system.

https://en.wikipedia.org/wiki/Cellular_senescence

Put otherwise, there is no free lunch. Just compromises.

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I don't know. Evolution doesn't seem to optimize for longer lifespans. So it would not optimize for substances that aid it.

Long lifespan is usually not in the interest of the species. While it's very much in the interest of individual and worth pursuing.

You are correct. But it's also a probability distribution game. Increase probability to get cancer at advanced age, you will also increase it (maybe just a bit) for the younger population.

>>Evolution doesn't seem to optimize for longer lifespans.

Not quite true (if not weighting high on optimization). There are multiple species which are outliers by lifespan in their niches: whales, hydras, etc. Even within rodent family there is a wide range of lifespans typical for a species - from ~2 years for a mouse to ~30 years for a naked mole rat.

There are regenerative species with incredibly messy genomes which are biologically immortal. So relying on evolution as a main explanatory principle is not comprehensive enough (especially given that you can't currently reverse engineer much of the evolution subjects).

>>Surely there are downsides (cancer, ...)

Me doesn't quite understand the rationale behind this widely used argument. Ok, senescent cells emerge as a mechanism to ward off cancer. They are basically semi-cancerous cells with an arrested cell division cycle ("zombies"). The goal of cancer therapies is to eliminate cancer cells. So what's wrong with the elimination of senescent cells? (especially if you get new stem cells differentiating into new healthy tissue in place of senescent ones or let the surrounding healthy tissue to proliferate there)

There is nothing wrong with eliminating them. But this study says psylocybin slows down cells becoming senescent, not that it eliminates them. So in fact it makes them live longer.

Yep, they show it's not a senolytic, but I'd like to see an experimental human group (preferably with a dopamine transporter allele making them more prone to placebo-like responses) being given psilocybin and told that it is a senolytic.

"Psilocybin treatment led to a dose-dependent decrease in cell cycle arrest markers (p21, p16, and p53) and an increase in markers of DNA replication (phosphorylated-Retinoblastoma protein; pRB) and proliferation (PCNA), as compared to vehicle-treated cells". They don't say it IS carcinogenic. At least this statement favors taking psilocybin after fasting/senolytics/autophagy induction.

"may mediate SIRT1-dependent pathways which impact cellular senescence". So if senescence is delayed by it and during this period SIRTs are activated, it may be anti-cancerous.

Anti-oxidants prevent cell damage caused by reactive oxygen. People thought that's a good thing. But it turns out that can actually promote cancer, because cells expect to be damaged in time, and kill themselves when that happens, and anti-oxidants mess with this mechanism.

> Some of the largest clinical trials, in fact, had to be aborted because the patients receiving antioxidants had a higher incidence of cancer than patients who did not receive them.

https://www.cancer.gov/news-events/cancer-currents-blog/2015...

Preventing cellular senescence sounds like the same kind of thing, messing with an existing mechanism put in place to prevent cancer.

I heard about this anti-oxidant hype, so the original psilocybin study now seems a bit incomplete.

There are a ~dozen of studies on dasatinib (anti-cancer drug) + quercetin (senolytic) for curing osteoarthritis in humans, improving heart tissue etc, with dasatinib used as a senolytic. Navitoclax (anti-cancer drug) also used as senolytic in some studies.

In this context it seems that adverse effects from senolytics may be more pronounced in cancer-prone, in younger age or if taking them continuously (not like 5 days per month or so letting some senescent cells to emerge). Yet Sinclair's new venture TallyHealth, for example, are selling a 5 in one capsule, containing apart from other stuff 500 mg quercetin and 100 mg fisetin (senolytics) with an expectation of daily intake. And his 80y old dad is taking senolytics daily with still no cancer.

> are selling a 5 in one capsule

As long as it's not known to be dangerous, people are free to experiment. But they should make it clear that there are no comprehensive studies showing an improvement, just speculation based on mechanics and some animal studies.

Another example is NAD+, people messing around with billion years old hyper-conserved mechanism (citric acid cycle). What could possibly go wrong, right?

Ion channels are also a hyper-conserved mechanism as every cell needs to maintain a resting potential, and there are tons of ion channel modulating drugs approved and used messing with the with billion years old hyper-conserved mechanism.

I heard about NAD+ on Dave Asprey podcast, that with age the NAD cleavage system cleaving NAD excess is also degraded and a Nuchido company makes this supplement with additives targeting NAD cleavage system restore as well.

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