Here Richard Miller points out that the 4 common anti aging drugs, as well as CR , all share common pathways.
Average and maximal lifespan can be increased in mice, in one or both sexes, by four drugs: rapamycin, acarbose, 17a-estradiol, and canagliflozin. We show here that these four drugs, as well as a calorie-restricted diet, can induce a common set of changes in fat, macrophages, plasma, muscle, and brain when evaluated in young adults at 12 months of age. These shared traits include an increase in uncoupling protein UCP1 in brown fat and in subcutaneous and intra-abdominal white fat, a decline in proinflammatory M1 macrophages and corresponding increase in anti-inflammatory M2 macrophages, an increase in muscle fibronectin type III domain containing 5 (FNDC5) and its cleavage product irisin, and higher levels of doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) in brain. Each of these proteins is thought to play a role in one or more age-related diseases, including metabolic, inflammatory, and neurodegenerative diseases. We have previously shown that the same suite of changes is seen in each of four varieties of slow-aging single-gene mutant mice. We propose that these changes may be a part of a shared common pathway that is seen in slow-aging mice whether the delayed aging is due to a mutation, a low-calorie diet, or a drug.
Average and maximal lifespan can be increased in mice, in one or both sexes, by four drugs: rapamycin, acarbose, 17a-estradiol, and canagliflozin.
The takeaway for me is the second sentence:
We show here that these four drugs, as well as a calorie-restricted diet, can induce a common set of changes in fat, macrophages, plasma, muscle, and brain when evaluated in young adults at 12 months of age.
Still seems to be the Holy Grail - how to replicate the effects of CR without starving. Is it Valter Longoâs fasting-mimicking diet? Dr. Annette Bosworthâs protocol? Some other variation?
I guess thereâs two ways to look at it. If youâre having side effects from rapamycin, you can add on one of the other drugs . If no side effects, just increase rapa.
It does call into question whether glucose lowering is pertinent to the anti aging effects. Doesnât look like it from this paper.
Where does the ITP announce the latest compounds they will be testing? I think the cutoff was the end of February to submit ideas, have they announced what they will test this year?
Time-restricted feeding has many of the same benefits as CR diets.
Most people will not adhere to a long-term CR diet.
Time-restricted feeding TRF is easily learned and much easier to maintain.
I started delaying my breakfast 1 hour a day, staying at that level for a few days then increasing the time by another hour until I reached my goal of a 16/8 feeding window.
Now I could easily do one meal a day except that I feel uncomfortable taking all of my calories in one meal. My current feeding window is 19/5. I eat between 12-5 pm.
I am also on rapamycin and canagliflozin. I donât do acarbose because I donât like the digestive side effects.
âIntermittent fasting and time-restricted eating role in dietary interventions and precision nutritionâ
âObese adults practicing time-restricted eating (TRE) for 8 h each day for 12 weeks lost weight had a lower systolic blood pressure through a mild CR without calorie countingâ
As people know my hypothesis is that the main aging pathway is through the failure to express long genes. This has two causes both of which result in a shortage of Acetyl-CoA in the nucleus. (inefficient mitochondria and senescence).
However, whatever the core aging pathway is there would logically be ways of attacking that which are additive. The four drugs (and I only know Rapamycin well) could be additive, or could really not make that much difference.
However, it is entirely possible that it is better to take Rapamycin and one of the other drugs rather than more Rapamycin.
I canât see the full article but from what people have quoted and the little I see it doesnât seem to indicate that one of those drugs hits all the pathways. Is that stated in there somewhere that rapa or another drug hits all the pathways on its own?
The study is stating that all 4 drugs are having the same effects on multiple tissue types and perhaps via the same common pathway.
If acarbose, for instance, is just additive to rapamycin, then why not just up the dose of rapamycin. If itâs a synergy, acting through a separate pathway, then adding it makes sense to me, but only if the pathways are different.
I think rapa/acarbose/17-a-e are clearly different drugs with different mechanisms. I highly doubt it is all via the same pathway.
I donât think itâs a good idea to keep increasing rapa dose âuntil you get side effectsâ, when we are talking about those encountered in the Mannick 2014 paper.
I donât think that IF can produce autophagy. That always seemed the prime benefit for long-term fasting, whether water fasting or Victor Longoâs equivalent. That is what attracted me to rapamycin initially.
I think you are over reading this. My understanding is that the purpose of this study was to look at the areas where all of the drugs overlapped. The drugs donât overlap in all areas and thereâs no implication that they arenât beneficial in the areas where they do not overlap. They are just trying to improve their hit rate on new molecules.
What makes me mad is the article is not available, and Richard Miller is 100% supported by tax payer dollars. It is a racket. I take all of them except the 17-a-e. Would like someone to comment on that drug and what it has done for them. Acarbose and Canagliflozin reduce glucose in the blood which Rapa has a limited effect on. Reducing glucose and the inflammation that goes with it is crucial in living a long and healthy life.
Itâs a good point that thereâs not 100% overlap, but are the areas that do overlap have the greatest impact on aging?
Why is there so much overlap in widely varying drugs?
There may be benefits in other modes of action, like the microbiome, but itâs not clear.
Thereâs also evidence that each of these drugs inhibit mTOR, at least in some tissues.