Canagliflozin - Another Top Anti-aging Drug

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RapAdmin (or anyone else), do you have any sense when the next wave of ITP results will go public?

(Last year I think they were out by now and the year before that I think they were out by February or so.)

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No - its really hard to predict when they will announce results… I spoke with Richard Miller last year and he said this:

I, and all the people working on the ITP, want as much information to become public as soon as possible. We almost always present interim findings at meetings a year or more before the final publication goes into the review process. We have clear rules: when half the controls of each sex die at each site, we send the raw data and graphics to all scientists whose drug was tested in that cohort, and they are allowed (encouraged) to present it at meetings, use it in grants, etc., as long as they don’t use it for an official peer-reviewed paper. We then do a second analysis when we hit the 90th percentile for controls at each site for each sex - these data, too, go to all collaborators, for discussion in blogs, interviews, meetings, posters, etc. - just not in peer-reviewed publications until the ‘official’ ITP lifespan paper is accepted somewhere, with all of the year’s collaborators serving as coauthors so they get the credit they deserve.

I may ping him and the rest of the ITP group to see if there are any updates they can provide.

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Got it. Thanks a bunch for this color.

(And yes please do ping; personally extra interested in the dimethyl fumarate results given the past success of the the nrf2 / protandim supplement

Perhaps there have been some of the “50% death” milestone results in some of the studies that we have missed here because they were only meeting abstracts and not published paper(s))

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The way you wrote this made it sound (to me) as if you were saying that there is evidence that SGLT2i have a glycemic-independent protective effect against tumors. But the cited paper actually raises concerns that they might increase the risk:

The more common complications include … off-target adverse reactions (including fracture, lower limb amputation risk and tumor). …

A previous study [80, 81] indicated that canagliflozin increased the risk of developing renal tubule tumors, pheochromocytomas and testicular Leydig cell tumors in rats. The mechanism may be related to the inhibition of intestinal carbohydrate absorption, the increase in calcium excretion in renal tubules and the synthesis of luteinizing hormone induced by canagliflozin. However, there are differences between animals and people, and animal models cannot completely replace clinical research. Further clinical trials showed that the risk of bladder cancer and breast cancer in the dapagliflozin treatment group was higher than that in the control group [82]. However, the study did not conduct tumor screening and could not determine whether the tumor was caused by dapagliflozin treatment. Therefore, there is still controversy about whether SGLT2i can induce tumorigenesis.

There’s no obvious effect one way or the other in the main ITP report:

However, if similar percentages of cana v. control animals died of cancer it might suggest that cana delays their onset or slows progression, since it would take longer to kill a longer-living animal of the same disease.


In the Discussion, they note:

In preclinical studies, Cana administered at high doses to rats increased the frequency of adrenal and renal tubular tumors, and induced Leydig cell hyperplasia and adenomas at all doses in male mice (38). In a recent meta-analysis, however, SGTL2i use in humans was not associated with an overall increased cancer risk, and Cana specifically was associated with a reduced risk of gastrointestinal cancer (39).

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Good catch, yes, it seems I could have worded that better.

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update, I tried it again and I ended up getting a sever urinary tract infection, blood in the urine. Nothing eles in my protocol changed. I take Rapa and Canagiflozin. I will try Acarbose, once the infection clears.

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I find that surprising that you got a UTI as a male… I’ve never heard of that happening. Can I ask what your daily diet consists of typically? I do know that SGLT2 inhibitors increase risk of UTI, but I was thinking that was primarily a female issue. My pharmacist friend suggested that since there is increased sugar in your urine, and bacteria love sugar, that the reason for the risk is the way the sugar is disposed of. I’m wondering if a low to moderate carb diet with canagliflozin is best?

Perhaps taking Cranberry juice with canagliflozin is the answer?

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Open Access Paper:

Vascular aging is an important factor contributing to cardiovascular diseases, such as hypertension and atherosclerosis. Hyperlipidemia or fatty accumulation may play an important role in vascular aging and cardiovascular diseases. Canagliflozin (CAN), a sodium-glucose cotransporter inhibitor, can exert a cardiovascular protection effect that is likely independent of its hypoglycemic activities; however, the exact mechanisms remain undetermined. We hypothesized that CAN might have protective effects on blood vessels by regulating vascular aging induced by hyperlipidemia or fatty accumulation in blood vessel walls. In this study, which was undertaken on the basis of aging and inflammation, we investigated the protective effects and mechanisms of CAN in human umbilical vein endothelial cells induced by palmitic acid. We found that CAN could delay vascular aging, reduce the secretion of the senescence-associated secretory phenotype (SASP) and protect DNA from damage, as well as exerting an effect on the cell cycle of senescent cells. These actions likely occur through the attenuation of the excess reactive oxygen species (ROS) produced in vascular endothelial cells and/or down-regulation of the p38/JNK signaling pathway. In summary, our study revealed a new role for CAN as one of the sodium-dependent glucose transporter 2 inhibitors in delaying lipotoxicity-induced vascular aging by targeting the ROS/p38/JNK pathway, giving new medicinal value to CAN and providing novel therapeutic ideas for delaying vascular aging in patients with dyslipidemia.

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The US Food and Drug Administration (FDA) has expanded the indication of dapagliflozin (Farxiga, AstraZeneca) to include treatment of heart failure (HF) across the full spectrum of left-ventricular ejection fraction (LVEF) ― including HF with mildly reduced ejection fraction (HFmrEF) and with preserved ejection fraction (HFpEF).

The sodium-glucose cotransporter 2 (SGLT2) inhibitor was previously approved in the US for adults with heart failure with reduced ejection fraction (HFrEF).

The expanded indication is based on data from the phase 3 DELIVER trial, which showed clear clinical benefits of the SGLT2 inhibitor for patients with HF regardless of left-ventricular function, as reported previously by theheart.org | Medscape Cardiology.

https://www.medscape.com/viewarticle/991736

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Canagliflozin still appears to be the better drug for diabetes control.
Empagliflozin is possibly better than either canagliflozin or dapagliflozin for heart problems.
It’s difficult to determine which is best overall. I guess it depends on one’s particular health issues.

“The model predicted longer survival for empagliflozin versus canagliflozin, dapagliflozin
“Conclusions”
In healthy participants, canagliflozin 300 mg provided greater 24-h UGE, a lower RTG and smaller PPG excursions than dapagliflozin 10 mg.”

https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.12418

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I am very concerned about the Klotho target protein, as it is an extremely important and critical marker for anti-aging. Of course, a few years ago, papers pointed out that FGF23 protein is the key to klotho protein. However, according to this paper, whether it is FGF23 protein or klotho protein, the effect of canagliflozin is better than that of empagliflozin.

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Excellent article, thank you.

I saw a recent post on here about Canagliflozen negatively impacting bone density in mice. Was that removed? Searching for it but nothing is coming up.

Its here: Canagliflozin Compromizes Bone Morphology and Density and Increases Fracture Risk In Mice and Humans

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@baimayangji can you elaborate on your concerns? It seems up-regulation of KL would be a good thing at least in the setting of APOE4 variant Alzheimer’s in the brain. I’m guessing likely SGLT2 inhibitors don’t cross the BBB though.

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According to the conclusion of the paper, it seems that Canagliflozen can increase the expression of klotho protein

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“Empagliflozin has an antiaging effect, which may be related to reducing Sirt1-mediated oxidative stress.”
Can’t have too many anti-aging compounds, just ask Bryan Johnson. :smile:

I wasn’t aware that Empagliflozin upregulated Sirt1. I have a bunch in my cabinet because I stopped taking it because it didn’t seem to have much effect on my blood glucose levels.
I guess I will start taking it again.

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Not sure about side-effect/risk side of the equation, but it does seem like there may be a a lot more in addition to glucose modulation

And Prof Nir Barzilai together with a former key director at NIA ranks Cana at the very top of a ranking of gerotherapeutics potential in humans - ahead of not only metformin, but also ahead of rapa and acarbose…. See eg Table 1 here

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13596

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