Very nice writeup on pioglitazone, though notably lacking in one of the biggest concerns: increased incidence of bladder cancer, which is strongly correlated both dose and time dependent. I too have explored pioglitazone (Work In Progress) in this thread:
I also think it’s pretty important to look at combining use of pioglitazone and other drugs. Statins, which you mention, but also telmisartan which has several possible synergies while possibly alleviating some of the undesirable side effects, such as weight gain. Also, SGLT2i, such as empagliflozin which might reduce edema and perhaps lower the HF danger.
As always, healthy aging and life prolongation is complex and unlikely for any single drug to have optimal effectiveness alone. Instead, carefully calibrated polypharmacy is called for, adjusted depending on one’s particular phenotype.
Atm, I’m doing lipid lowering therapy (pitavastatin, bempedoic acid, ezetimibe), glucose control (empagliflozin), BP control (telmisartan), and soon low dose (7.5mg/day) pioglitazone. Epicatechin I’m hoping to cover through dietary sources, daily cacao and green tea. And of course, rapamycin - 6mg/1-week. To the degree that I could, I’ve explored the possible interactions of these various molecules, but naturally, it’s a continuing and never ceasing work in progress (WIP).
I’ve been on Rosuvastatin (2.5mg), Lisinopril 10mg, Aspirin 80mg. Added ezetimibe on and off (still trying to get used to it). Pio 7.5mg is great but I think I’m getting too much bone marrow supression these days (so I’m not on it).
I wonder about EGCG, also. It has been claimed to inhibit DYRK1A, one of the genes influencing the DREAM Network (so does EGCG result in an increase in DNA repair?), though I’m not sure the same is true of plain epicatechin.
The results from the ITP (Intervention Testing Program) can absolutely be seen as a strong signal that excessive insulin signaling (hyperinsulinemia) is a key accelerator of mammalian aging. This aligns very well with Dr. Ben Bikman’s reasoning and the broader scientific understanding of the insulin/IGF-1 signaling pathway in aging. Insulin levels can be seen as the canary in the coal mine.
ITP, some of us here and biogerontologists know that the Insulin/Insulin-like Growth Factor 1 Signaling pathway is one of the most evolutionarily conserved pathways regulating aging. Reduced signaling in this pathway is strongly associated with increased lifespan and healthspan in species from worms and flies to mice. And some say that, low insulin signals is strongly associated with increased lifespan and healthspan even in long lived humans.
Excessive signaling is associated with accelerated aging and age-related diseases.Insulin is Not the Enemy, Hyper-insulinemia Is. Insulin is an essential anabolic hormone. We need it to live. The problem is the chronic, excessive levels. The ITP provides strong correlative signal for this reasoning.
But these drugs (drugs for type 2 diabetes) have other proposed anti-aging effects, like effects on mitochondria, AMPK activation, that may be independent of insulin. Lower insulin likely contributes to these other beneficial effects. High insulin activates besides IGF also mTOR.
Other concentrations will need to be tested, but based on the available evidence, acarbose is the antidiabetic drug with the greatest impact on lifespan in mice and with fewer potentially harmful side effects.”
I have been eagerly awaiting the forskolin results, as I take it as part of my bone building regimen and I wanted reassurance that it isn’t negatively affecting my longevity, as there seem to be no previous experiments where mammals have been fed forskolin for their entire life. I got that reassurance, at least, but looking deeper, it seems they tested it at a relatively low concentration of 8ppm in the chow, which translates to a significantly lower dose than many people take. 8ppm translates to less than 1 mg/kg/day, yes? I take 100 mg/day. They state in the paper, “We note, however, that FSK increased median survival of males by ~ 8%, although this did not reach statistical significance. It is possible that testing FSK at other doses might produce more impressive effects.”
Not at all. These are very different drugs. Pioglitazone is an old drug well known to act through activating PPARgamma. Mitoglitazone does not activate PPARgamma at all (at least not directly and probably not indirectly either to a significant extent). The fact that they both share the glitazone nomenclature can be misleading because it is a reflection of their similar chemical structure rather than of their mechanism of action. Similar chemical structure does not mean similar mechanism of action however.
Yes and no in this case. Pio (and I think the rest of the common glitazones) hits both the mitochondrial target and PPARg. The antidiabetic effect is speculated to come from both sources. Mitoglitazone is a tiny structural modification of Pio that somehow disables the PPAR activity, without being notably more or less active at the mpc, iirc.
