Anti-Aging Drugs and the Related Signal Pathways

[RapAdmin]

A fairly concise review of six anti-aging pathways and the drugs which affect them, including acarbose, lithium, metformin, NAD+, NSAIDs, metformin and rapamycin.

Aging is a multifactorial biological process involving chronic diseases that manifest from the molecular level to the systemic level. From its inception to 31 May 2022, this study searched the PubMed, Web of Science, EBSCO, and Cochrane library databases to identify relevant research from 15,983 articles. Multiple approaches have been employed to combat aging, such as dietary restriction (DR), exercise, exchanging circulating factors, gene therapy, and anti-aging drugs. Among them, anti-aging drugs are advantageous in their ease of adherence and wide prevalence. Despite a shared functional output of aging alleviation, the current anti-aging drugs target different signal pathways that frequently cross-talk with each other. At present, six important signal pathways were identified as being critical in the aging process, including pathways for the mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), nutrient signal pathway, silent information regulator factor 2-related enzyme 1 (SIRT1), regulation of telomere length and glycogen synthase kinase-3 (GSK-3), and energy metabolism. These signal pathways could be targeted by many anti-aging drugs, with the corresponding representatives of rapamycin, metformin, acarbose, nicotinamide adenine dinucleotide (NAD+), lithium, and nonsteroidal anti-inflammatory drugs (NSAIDs), respectively. This review summarized these important aging-related signal pathways and their representative targeting drugs in attempts to obtain insights into and promote the development of mechanism-based anti-aging strategies.

Full paper, Open Access: Biomedicines | Free Full-Text | Anti-Aging Drugs and the Related Signal Pathways

Figure 2. Rapamycin and the aging-related mTOR signal pathway. This figure shows several signal pathways downstream of rapamycin. Rapamycin mainly functions through mTOR and their downstream molecules, such as DAF-16/FoxO and Nrf2/SKN-1, to regulate protein homeostasis, PGC-1α to influence mitochondrial respiration, ULK1 and p73to regulate autophagy, and HIF1α to inhibit ER stress, aiming to regulate longevity.

Figure 4. Acarbose and the aging-related nutrient signal pathways. This figure shows several signal pathways downstream of acarbose. Acarbose may change the gut microbiota, insulin/IGF-1 receptors, and ATF4 to regulate lifespan.

[Neo]

Likes the figures so thought I’d also paste these ones:

Has the lithium => telomere link been discussed before on the forum?

And

[Joseph_Lavelle]

Nice.

Did you notice that only NMN and Metformin had a single point of entry into mechanism of beneficial action? And NMN appears to only increase NAD+ which can be done a number of ways (NR, coffee, niacin, Nicatinamide, etc).

NCAIDs include aspirin plus a bunch of stuff I wouldn’t take (ibuprofen etc).

[Neo]

@Joseph_Lavelle

NCAIDs include aspirin plus a bunch of stuff I wouldn’t take (ibuprofen etc).

Are you hesitant around aspirin also - or about the other stuff like ibuprofen?

[Joseph_Lavelle]

I take aspirin now but with some hesitation. It’s the oldest yes/ no switcher-oo in the book. I used to take vitamin I (ibuprofen) before, during, and after skiing, rock climbing, weight lifting, etc. I’ll never take another one.

[Neo]

I’m thinking of doing a small does perhaps 3 times a week. Do you think one should move it away from when doing stretch training or do in conjunction to such training?

[Joseph_Lavelle]

Ibuprofen? No way. I’d look into circumin, fish oil, green tea, ginger… if you need something anti-inflammatory. It’s the chronic inflammation that’s the problem not the acute. You want to heal and adapt to stressors. If you are older make sure your glutathione production has the glycine and cysteine needed. Also make sure NO is solid. If your hsCRP is low then maybe you are good as is.

[Neo]

Sorry, meant aspirin. Would you do it away or in connection to strength training.

The reasons I’m thinking of it of not connected to exercise per se, but from both a longevity perspective (ITP and eg the paper that started this thread, etc) and a decreasing odds of certain cancers perspective (discussed several places on this forum).

Idea would be to do it for perhaps a decade (while evaluating new science along the way) and if conclusions from science have not changed then I’d probably stop as I get older and the downside risks seem to go up (I’m 45 now).

Now my question now is more just about when during the week I want to take the 3 small doses - away from or after weightlifting.

(My blood markers of inflammation are all low: hs-CRP is below the threshold, ERS, IL 6 also low, except perhaps for homocysteine at 9.5 that is “in normal range, but not low - but I can sometimes feel pain in my finger joints or knees in a smaller degree/direction of what I could imagine early arthritis might feel like / as if there is some form of inflammation).

[Joseph_Lavelle]

Oh sorry. Yes, I take aspirin for the longevity benefits that I hope are there for me. I don’t see it as a “no-brainer”…it’s a pick 'em supplement in my opinion. I’m choosing yes for now. I only take a baby aspirin every other day. I take an enteric coated aspirin, but I intend to switch to a non-coated aspirin soon for better absorption. I’ll see if I get some stomach issue or not.

[Neo]

So basically approach is every other day and not marched into your 14 day cycle with days of strength and more protein vs no such days?

[Joseph_Lavelle]

I hadn’t thought about it that hard, but now you made me think about it…, so I will start cycling it into my existing EOD lifting cycle (take aspirin in the 24 hours before lifting, not the 24 hours after lifting). Thanks.

[DrRoss]

In the 2nd edition of my rapamycin book, I proposed the mTOR/Autophagy Theory of Aging. I think most people alive today are seriously out of balance in their mTRO/autophagy ratio…which is a significant factor in mankind’s current epidemic of epidemics. Ross

[RobTuck]

This is an excellent review and summary article. The comparison table is a good communications tool for newcomers to the topic. Thanks for presenting it.

[John_Maccorkindale]

Food for thought. For those of us with egfr’s of 60 or lower remember that nsaids like aspirin, Aleve, etc can exacerbate our chronic kidney disease so look for alternatives. Johnmac

[Joseph_Lavelle]

@John_Maccorkindale Thanks. Dr Johnson said in my recent interview that aspirin (and Tylenol) was not a problem but I do see online that high dose aspirin is a problem for kidneys. This paper shows that a low dose aspirin has some positive (GFR) and some negative (sodium excretion) effects on kidney function. And, while there are other reasons a reasonable person might choose to take or avoid low dose aspirin, it seems to me that regular high dose aspirin would be a mistake.

https://onlinelibrary.wiley.com/doi/full/10.1016/j.ejheart.2008.06.014