Hello Andy! Brandon and Rich here from the Healthspan Clinical Team to weigh in on this question about protocol pairings to best maximize metabolic health. It’s essential to consider a multifactorial model that integrates biochemical, physiological, functional, and lifestyle domains, but in this case, we’ll be zeroing in on the blood glucose component. Tough to answer definitively, sure, but let’s give it a go!
It seems like you have done your homework, but just to lay the framework for discussion:
- Low-dose oral rapamycin inhibits mTORC1. Low-dose intermittent use improves insulin resistance, enhances autophagy, reduces age-related inflammation and fibrosis, while supporting immune system performanceim.
- Acarbose inhibits intestinal α-glucosidases, delaying glucose absorption in the small intestine, flattening postprandial glucose spikes. This improves postprandial glycemic control, reduces insulin demand, and may mimic caloric restriction and promote healthy gut microbiome.
- SGLT2i’s inhibit sodium-glucose co-transporter 2 (SGLT2) in the kidney, reducing glucose reabsorption and increasing urinary glucose excretion (glycosuria). This lowers blood glucose and insulin levels, induces mild caloric loss, promotes fat burning, ketogenesis and improves cardiovascular and kidney disease risk. and
If you put a pretty bowtie knowing only this information about these three molecules, you could succinctly say: together, they reduce glucose input (acarbose), increase glucose output (SGLT2i), and improve intracellular glucose handling (rapamycin). Sounds like a glucose-burden alleviation cocktail if you ask me! But, the most bang for the buck is also a consideration.
For those unfamiliar with the ITP, this refers to the National Institute on Aging Interventions Testing Program (ITP), which was designed to be the most exhaustive testing framework and system to evaluate whether longevity molecules extend longevity in mice and understand the underlying mechanisms leading to those benefits. This is the gold standard for longevity drug testing involving multiple research laboratories. These labs evaluated a selection of promising longevity molecules, including rapamycin, metformin, nicotinamide riboside, and the SGLT-2 inhibitor canagliflozin, among others.
At the end of the study, only five of the molecules that the ITP studied were shown to increase longevity. One of the most eye-opening findings was the results of acarbose [1,2].
The ITP showed that acarbose increased lifespan in the animal model they were studying. When acarbose was combined with the mTOR inhibitor rapamycin, it significantly increased lifespan, which was even more pronounced than when acarbose was used alone.
The researchers evaluated the effect of rapamycin and acarbose in combination given to mice starting at either 9 or 16 months. The 9-month mice had the most remarkable results, increasing the medium lifespan of female and male mice by 28% and 34%, respectively. The 16-month mice still increased the medium lifespan of both female and male mice by 13%. Moreover, out of 14 longevity molecules, the combination of rapamycin and acarbose was 2 of the 5 longevity molecules that extended lifespan. In three independent trials, the combination extended lifespan by 22%.
In another study of all longevity molecules, the combination of rapamycin and acarbose had the largest increase in lifespan—this has been seen in nearly all mammalian species, an average of 30% life extension.
Rapamycin is considered one of the most potent and well-studied pharmacological interventions for anti-aging. Rapamycin exerts its anti-aging effects by inhibiting the mammalian target of rapamycin (mTOR) pathway.
The mTOR pathway is a central cell growth, proliferation, and metabolism regulator. By modulating this central regulator, Rapamycin can promote cellular processes important for longevity and healthy aging, such as enhanced autophagy, reduced inflammation, and improved cellular resistance. [3]
Acarbose induces anti-aging mechanisms that complement Rapamycin’s implementation. Both medications operate similarly by acting as calorie restriction (CR) mimetics. Acarbose reduces postprandial glucose spikes and insulin levels. Lowering insulin and glucose levels is a hallmark of CR and has been linked to longevity [4]. Rapamycin leverages mTOR inhibition as a CR mimetic. Hence, Acarbose and Rapamycin, through their distinct mechanisms of action, can influence important metabolic and signaling changes linked to CR.
As for the SGLT2, the ITP data were strongest for male mice. One study aimed to evaluate canagliflozin for its impact on lifespan in male and female genetically heterogeneous mice as part of the NIH Interventions Testing Program. Male mice experienced a ~14% increase in median lifespan when treated with canagliflozin compared to controls [5]. However, female mice saw no significant extension in lifespan under the same treatment. Canagliflozin was shown to modulate key longevity pathways, including activation of AMPK (promoting energy balance), suppression of mTOR signaling, and increased levels of FGF21 (a metabolic regulator). This demonstrated that canagliflozin could act as a geroprotective agent, having some mechanistic overlap with rapamycin. SGLT‑2 inhibitors are being investigated for healthspan extension, beyond their common use in type 2 diabetes and cardiovascular health benefits.
Rapamycin, acarbose, and SGLT-2 inhibitors are arguably the top three most promising longevity molecules to emerge from the ITP so far.
What would Brandon/Rich do? (WWBRD?)
- Let your personal health data guide your decision making - and also reach out to us within your patient portal - we twiddle our thumbs without engagement from you (mostly joking).
- Involve your provider and clinical care team to make sure you are safe
- Leverage molecules systematically and titrate dose to find the best fit for you
- Avoid adding multiple new protocols simultaneously so you can assess the effects of each and the combination impact effectively
- Check back in regularly with lab results especially for rapamycin and SGLT2i, which include routine labs as part of your protocol
Sources:
[1] Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer - PMC
[2] Healthspan Research Review | Exploring the Anti-aging Potential of Acarbose and Rapamycin: Insights from the NIA Interventions Testing Program
[3] https://onlinelibrary.wiley.com/doi/10.1111/gbb.12109
[4] Frontiers | Intestinal Short Chain Fatty Acids and their Link with Diet and Human Health
[5] Canagliflozin extends life span in genetically heterogeneous male but not female mice - PMC
