SGLT2 Inhibitor Canagliflozin eliminates senescent cells and alleviates pathological aging (in mice)

https://www.nature.com/articles/s43587-024-00642-y

It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium–glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.

Hypothalamic sex-specific metabolic shift by canagliflozin during aging | GeroScience.

We studied the long- and short-term effects of Cana on hypothalamic metabolic control in UM-HET3 mice. Starting the treatment from 7 months of age, we show that 4 weeks of Cana treatment significantly reduced body weight and fat mass in male but not female mice that was associated with enhanced glucose tolerance and insulin sensitivity observed by 12 months. Indirect calorimetry showed that Cana treatment increased energy expenditure in male, but not female mice, at 12 months of age. Long-term Cana treatment increased metabolic rates in both sexes, and markedly increasing formation of both orexigenic and anorexigenic projections to the paraventricular nucleus of the hypothalamus (PVH) mostly in females by 25 months. Hypothalamic RNA-sequencing analysis revealed increased sex-specific genes and signaling pathways related to insulin signaling, glycogen catabolic pathway, neuropeptide signaling, and mitochondrial function upregulated by Cana, with males showing a more pronounced and sustained effect on metabolic pathways at both age groups.

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@John_Hemming @DeStrider ans other senescence enthusiasts + @adssx @AnUser @RapAdmin

What are your thoughts on this? Perhaps this suggest one could cycle a period of Cana say 2-3 times a year or something





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So this should carry over to other more specific inhibitors of SGLT2 (dapa and empa) since I didn’t see any mention of SGLT1 in the above(?)

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I like it, @Neo That’s why I take empagliflozin daily. For me, it also helps with drinking more water and losing weight.

Since most senescent cells are found in adipose tissue (white fat), anything that helps you get rid of fat will reduce your senescent cell load. SGLT2I are a win-win in my book!

(You can also order brand name empagliflozin from India for a greatly reduced cost, not a generic Indian-made brand!)

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Perhaps, but only perhaps

There is some support from this other context re senescence of other flozins

AMPK might be more a Cana thing than other flozin wide thing though:

But there is also this line of thinking

To note, canagliflozin targets AMPK at a significantly higher level- It will be a no brainer when I specify the mechanism- inhibiting mitochondrial function, complex 1. As we all know, mice are vulnerable and prone to cancer; humans having much more complex systems than mice so far from equal models for ITP outcomes, but the cancer specific outcomes in humans are measurable.

Beyond, autoimmune targets for age-related, generalized autoimmunity is of interest as we currently cannot target the aging immune system in all its complexity- increasing immune responses is a problem leading to many diseases- presently, canagliflozin but not other SGLT2 inhibitors have shown to target adaptive related modulating effects rather than suppressing.

I have not read up on that, has anyone else? @DrFraser @Joseph_Lavelle @jnorm

Last quote blocks from

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This a complex one, and I’ll wimp out and go with AI on this one. However, Canagliflozin has unique activity the others don’t. I guess if you are going to be on an SGLT2i, possibly consider this. However, in my writeup on these, it appeared to be less impressive and inferior to the other agents in class for dementia reduction. Article on this

Current evidence does not clearly indicate that canagliflozin is superior to other SGLT2 inhibitors in reducing death, malignancy, or cancer risk. All SGLT2 inhibitors, including canagliflozin, have demonstrated benefits in reducing cardiovascular death and all-cause mortality in patients with type 2 diabetes and high cardiovascular risk. However, no specific SGLT2 inhibitor, including canagliflozin, has been shown to be superior in these outcomes. The CANVAS program reported a 13% reduction in cardiovascular death risk with canagliflozin, but similar benefits have been observed with other SGLT2 inhibitors like empagliflozin and dapagliflozin 1.

Regarding malignancy and cancer, the evidence is limited and inconclusive. A meta-analysis found no significant increase in overall cancer risk with SGLT2 inhibitors, and the CANVAS program reported no significant difference in cancer rates between canagliflozin and placebo groups. Concerns about specific cancer types, such as bladder and breast cancer, have not been substantiated in long-term studies, and no significant association has been found between SGLT2 inhibitors and these cancers 2.

In summary, while canagliflozin is effective in reducing cardiovascular mortality, it does not appear to be superior to other SGLT2 inhibitors in decreasing death, malignancy, or cancer risk. More comprehensive studies are needed to establish any potential differences among SGLT2 inhibitors in these outcomes.

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The AI is not incorporating anything about senescence or longevity here though

Will take a look at your blog, thanks for sharing.

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One protocol could be to switch to Cana for a few weeks a few times a year and hedge in case Empa is not driving clearance of senescent cells.

I’m thinking of going between Cana and no Cana a few times per year. (And then calibrating as more data comes out)

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Do you have a link to the paper?

I think a lot of senescent cells are stem cells that have failed to differentiate and are best helped to differentiate.

Sure:

It’s the paper that the thread was started with, see above

As a reminder, empagliflozin extends lifespan as well in mice (at a dose way too high, TBD if a lower dose would increase more): Empagliflozin rescues lifespan and liver senescence in naturally aged mice 2024 (“Further exploration discovered that empagliflozin increased the concentration of SCFAs, decreased the levels of the inflammatory factors TNF-α, IL-6, and CXCL9, and regulated the PI3K/AKT/P21 and AMPK/SIRT1/NF-κB pathways, which may represent the underlying mechanisms involved in these beneficial hepatic effects.”)

AMPK is also activated by dapagliflozin: Dapagliflozin restores autophagy and attenuates apoptosis via the AMPK/mTOR pathway in diabetic nephropathy rats and high glucose-induced HK-2 cells 2024

In C. elegans, no SGLT2 increased lifespan: Million Molecule Challenge Results and Leaderboard – Ora Biomedical, Inc. (But I think the dose was too high and I sponsored another experiment at 5 µM, my bet is on dapagliflozin)

So the case for canagliflozin over empagliflozin and dapagliflozin seems very weak to me. Even more so considering that dapagliflozin and empagliflozin have a better safety profile than canagliflozin and are linked to better outcomes in RCTs and association studies (including on dementia).

For cancer, this 2017 blog post (I have no idea how reliable it is) concludes:

Based on the above you could argue that we should chose between e.g. Dapagliflozin and Canagliflozin depending on the tumor size and glucose status in the body.
Therefore, Dapagliflozin may be more relevant for the very large tumors, while Canagliflozin may be more relevant for smaller tumors in people with high blood glucose levels (e.g. who do not follow a low-sugar diet and do not use other glucose lowering medication).

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@adssx Have we seen any Mendelian Ranomization for SGLT2i yet?

That we have that for SGLT1i (together with multi ITP studies on Cana vs the single somewhat weird one-off study on Empa) does still hold some weight in the direction of Cana if one’s goal is lifespan extension and longevity, and not just health improvement.

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You’re right; the SLGT1 MR study gives one point to canagliflozin.

For SGLT2, we have this one: Canagliflozin - Another Top Longevity Drug - #1067 by adssx “Our study supported that SGLT2 inhibition increases father’s attained age, cognitive function and intelligence, which was mediated through brain images of different brain regions.” (males only again!)

And for SGLT2 and CVD & MI, we have these:

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