SGLT inhibitors are a no-brainer:
I don’t think any other drugs tick all these boxes.
Any point stacking SGLT2i with GLP1RA?
It seems that the GLP-1RA + SGLT2i combination offers synergies and benefits in T2D and CKD but there’s not enough data to conclude yet. We know it’s safe though.
I’m not convinced lifelong GLP-1 administration is a good idea for healthy people at ideal body weight.
I see them more as a temporary tool to make cuts easy.
Plenty of evidence emerging they are beneficial for more than just fat loss imo
Despite their wife benefits, they might still be detrimental in some people such as those with optimal weights. Some GLP-1RAs also cause depression (semaglutide especially). And as far as I know there is no evidence that they extend lifespan in animals. So they’re wonderful drugs for obese and overweight people and people with diabetes or CKD but for others, so far, their benefits are unproven. In the phase 3 exenatide trial in Parkinson’s for instance, people on exenatide were slightly worse off than those on placebo. If Parkinson’s is a “disease of aging” then that’s not the type of result you want to see. That being said I think there is a wide intraclass variability among GLP-1RAs and it’s possible that the newest one (tirzepatide?) are better. Time will tell…
I wouldn’t bother with anything before semaglutide, and see no reason to use semaglutide over tirzepatide. I’m looking forward to more studies being done. We likely won’t see a lifespan study done until orally bioavailable small molecule orforglipron is out since people don’t want to inject mice. That, or some kind of autoinjector for mouse studies is invented.
For mechanistic reasons alone I would expect modern GLP1 to have a similar life-extending effect in mice as acarbose.
That’s very interesting, because I was thinking the opposite. I’m probably wrong. I see SGLT2i and acarbose as directly limiting glucose levels, mechanistically, so more on the same plane. And GLP1 hormonal pathway, different plane. But it’s likely I misunderstood.
Both GLP1 and acarbose prevent glucose spikes due to delayed digestion while SGLT2i increase the rate of glucose excretion.
Actually I forgot there’s this paper on some GLP1-RAs extending lifespan in C. Elegans: Calcium channel blockers reduce aging rate (ARDD video) - #2 by adssx
Delay differently? SGLT2i impact spikes (i.e.effect).
Bet they will try it once oral GLP-1 agonists are available.
I am mildly concerned about posting this article as it looks like it is written by AI. However,
From the article:
- Rapamycin remains the lifespan champion in laboratory animals and delivers measurable immune rejuvenation in older adults, yet its influence on multi-omic aging clocks is inconsistent—sometimes slowing, sometimes neutral, and occasionally accelerating DNAm age.
- Metformin lags on absolute lifespan in animals but shows more reproducible molecular age reversal in humans and primates, particularly within metabolic and neuro-inflammatory pathways.
- The divergence underscores that “living longer” and “aging slower” are not interchangeable metrics. Biological clocks capture intrinsic cellular wear, whereas rapamycin’s forte may lie in systemic remodeling of immunity and metabolism that extends survival without fully rewriting epigenetic history.
- For clinicians and start-ups, the message is nuanced: rapamycin suits short-term immune enhancement or late-life disease postponement; metformin suits chronic metabolic tuning with multi-tissue rejuvenation potential. Future trials combining mTOR modulation, AMPK activation, and next-generation GLP-1 therapies—while tracking diverse aging clocks—might finally align lifespan, healthspan, and molecular youthfulness in the same cohort.
Orforglipron appears to be becoming available from Chinese gray market sources, similar ones that are selling peptides.
After using metformin for a while I can’t say there is a discernible benefit. I mostly got it because it doesn’t interact with that enzyme that makes rapamycin more potent in the body when activated/inhibited (I forget its name.)
I’ve got some empagliflozin coming and I’m thinking I’ll remove the metformin, throw in empagliflozin and replace the metformin with berberine again.
I’ve tried berberine and metformin, and in my experience, it felt like berberine was an inferior analog to Metformin.
Berberine consistently outperforms it in terms of lifespan extension.
Could you reference those studies that show this? I don’t recall reading that before. I’m happy to change my mind with evidence.
Looking into it I was wrong. I’m not sure why I thought this.