If there’s a molecule whose chemical properties you know INTENSELY DEEPLY ON THE INSIDE (up to even electrophilicity/nucleophilicity/HOMO-LUMO diagrams of every location EVERYWHERE), what would it be?
for me the most impt molecules now are the polar amino acids (ESP lysine), all DNA bases (esp guanine), melatonin, ascorbic acid, dopamine, lutein (or general classes of carotenoids), methylene blue, 4-HNE, N(6)-carboxymethyl-L-lysine , MGO, glucosepane
also oxidized byproducts of dopamine
increase zinc to copper ratio AND magnesium to calcium ratio
RAPAMYCIN WITH GRAPEFRUIT:
According to a statement from the University of Chicago Medical Center in Chicago, Illinois, where study director and cancer specialist Ezra Cohen, MD, practices, the effect of grapefruit juice begins within a few hours of ingestion and wears off gradually after a few days. Although this effect has long been considered an overdose hazard, “We wanted to see if grapefruit juice can be used in a controlled fashion to increase the availability and efficacy of sirolimus,” explained Cohen in the statement.
As Cohen and colleagues reported in Clinical Cancer Research, the optimal cancer-fighting dose for those taking sirolimus alone was found to be about 90 mg per week. But because nausea, diarrhea, and other serious gastrointestinal problems developed at doses above 45 mg, patients were switched to 45-mg doses administered twice a week.
Optimal sirolimus doses for the other two groups, however, were much lower: Persons who took ketoconazole plus sirolimus needed only 16 mg per week of the latter to maintain the same blood levels of the drug. By comparison, the grapefruit juice drinkers needed between 25 and 35 mg of sirolimus per week. Sirolimus blood levels increased by 500% with ketoconazole and by 350% with ingestion of 8 ounces of grapefruit juice daily. Despite the slightly stronger drug-retention effect of ketoconazole, grapefruit juice has the advantage of being nontoxic.
Mikhail Blagosklonny
@Blagosklonny
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1/5 In 2014, I published “Koschei the immortal and anti-aging drugs” presenting anti-aging combo/recipe. Dr Alan Green named it Koschei formula and implemented in the clinic (by now he develops his own formula)
Mikhail Blagosklonny
@Blagosklonny
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2/5 Since that time, I have significantly updated the formula. One of notable change is Low Carb instead of Low Fat diet. Importantly, now there are many Koschei formulas depending on a particular person. It is addressed to MDs not patients.
Mikhail Blagosklonny
@Blagosklonny
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3/5 Before I publish them, I present here One personalized example, suited to me In order of importance on the next page:
Mikhail Blagosklonny
@Blagosklonny
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4/5 Rapamycin high dose intermittently Low-Carb or Low Carb/Cal diets, time-restricted, IF Physical exercise daily Sun, Sunbath/Vit D3 Metformin low/medium dose Angiotensin II inhibitors Aspirin low dose Lithium low dose DHEA, L-Ornithine NAD boosters PDE5 inhibitor
Mikhail Blagosklonny
@Blagosklonny
5/5 Other agents to consider: Alpha-estradiol for men when become clinically available Acarbose (if cannot adhere to Low carb diet) Fisetin Doxycyclin (once/twice a month) And other compounds depending on conditions
https://www.longevity.technology/an-antiaging-supplement-that-also-reduces-appetite/ => has a special form of B6 - pyridoxamine . Idk if this is worth the cost - most of these are standard ingredients. see https://academic.oup.com/hmg/article/24/19/5500/584016
it’s GLO-activator AND MG scavenger (Glyoxalase system - Wikipedia )
Metformin does almost as well - Inhibitory Effect of Metformin and Pyridoxamine in the Formation of Early, Intermediate and Advanced Glycation End-Products
https://onlinelibrary.wiley.com/doi/full/10.1111/1541-4337.12376 (SOME AMINES also cause AGEs too - eg hereocyclic amines), but carnosine has an amine group and many of the best AGE-inhibitors are full of amine groups
https://www.youtube.com/c/DrBradStanfield has A LOT (way more conservative/conscientious than I am tho)
on NAC:
Doris Loh
Mar0uch 1g8pg6gi, 1n2062oei1d1 ·
I have been asked on many occasions, whether I support the use of N-acetyl-l-cysteine (NAC) for viral infections during the current pandemic. My usual answer is the temporary use of NAC may be beneficial, but long-term use is not recommended. Why?
For that answer, I will show you two recent studies that may surprise you about the long-term effects of using antioxidants, especially potent, relatively novel ones like NAC.
A recent peer-reviewed large-scale study and meta-analysis by Wang and colleagues showed that higher intakes of fruit and vegetables were associated with lower mortality, with the risk reduction highest at about 5 servings of fruit and vegetables per day [1].
Wang and colleagues analyzed data from the Nurses’ Health Study and the Health Professionals Follow-Up Study that included more than 100,000 adults who were followed for up to 30 years. Both datasets included detailed dietary information repeatedly collected every two to four years. Wang et al. also compared their results with data on fruit and vegetable intake and death from an additional 26 studies that included atotal of about 1.9 million participants collected from 29 countries around the world [1].
The results of their study and analysis showed that higher intakes of most subgroups of fruits and vegetables were associated with lower mortality, with the exception of starchy vegetables such as peas and corn. Intakes of fruit juices and potatoes were not associated with total and cause-specific mortality [1].
What happens when individuals take more than 5 servings of fruit and vegetables per day? The data collected by the team revealed that more than 5 servings a day actually resulted in the highest mortality rate — an observation that was not specifically mentioned in their report (see diagram). Do you find it unusual that, similar to vitamin D3, there is an U or inverted J-curve for antioxidants also for all-cause mortality? Do you want to know why higher antioxidants from fruits and vegetables may contribute to reduction in healthspan and lifespan?
For an explanation on the biomolecular level, the recent peer-reviewed paper on how long-term administration of NAC actually increases mitochondrial dysfunction may be able to shed light on this seemingly paradoxical observation.
Peris and his team showed that chronic NAC supplementation becomes pro-oxidant and leads to oxidative stress. Mice fed NAC for 7 days at 1 mg/ml drinking water showed increased mitochondrial reactive oxygen species (ROS) production and reduced oxygen consumption in adipocytes [2]. In adipocytes, the increase in oxidative stress can prevent the browning of white adipose tissues, leading to higher levels of fat accumulation. Animals under chronic NAC supplementation had increased fat pad sizes [2]. Chronic NAC supplementation can result in brown adipose tissue (BAT) dysfunctions. N-acetylcysteine supplementation was found to blunt β3-AR stimulation–induced browning of white adipose tissue and reduced mitochondrial activity in brown adipose tissue due to increased ROS [2].
At this point, I need to alert you to the fact that the amounts used by Peris et al. in this experiment is extremely high; and a person would not be taking such a high amount of NAC under normal circumstances. It is possible that the scientists used a high amount so they can achieve the targeted effect within a relative short time frame of just 7 days, which is equivalent to about 280 human days [3]. The question one needs to ask, especially after the observation that increasing daily fruit/vegetable intake by about 2 servings to 7+ daily can increase mortality, is whether long-term supplementation with potent antioxidants will have the same cumulative effect. And if so, what are the possible mechanisms that can lead to oxidative stress, turning an antioxidant like NAC into a dangerous pro-oxidant that can cause mitochondrial dysfunction.
It is possible that when mitochondria is exposed to an excess level of antioxidants such as NAC, it will cause endogenous antioxidants like glutathione levels to also increase. When reduced glutathione levels become excessive, the disruption in GSH homeostasis can actually backfire. Why? Excess GSH will add electrons to oxygen, changing it into superoxide anion free radicals. This process is known as reductive stress, or stress from too many reducing agents. The diagram below explains the role of excess antioxidants causing reductive stress to induce mitochondrial dysfunctions [2].
Now at this time, I need to remind you that there is a huge difference between NAC, a synthetic newcomer and ancient molecules like ascorbic acid, which is not an antioxidant but a redox molecule, and melatonin the potent endogenous antioxidant that has evolved with all life forms for more than 3 billion years.
N-acetyl-cysteine (NAC) is an acetylated cysteine residue, a synthetic molecule with a very short history. Studies showed that the use of NAC changes the glutathione redox homeostasis to favor the increase of the reduced GSH form [4]. Whereas AA and MEL actually stimulate the production of total GSH, which would not skew the GSH/GSSG ratio to disrupt homeostasis [5].
I hope the post today helps you to understand why I rarely recommend the use of molecules that do not have an established history in evolution.
Have you had your AA and MEL today?*
- Disclaimer: These statements have not been evaluated by the Food and Drug Administration. Ascorbic acid, melatonin and any other product mentioned is not intended to diagnose, treat, cure or prevent any disease.
References:
Dong D. Wang, Yanping Li, Shilpa N. Bhupathiraju, Bernard A. Rosner, Qi Sun, Edward L. Giovannucci, Eric B. Rimm, JoAnn E. Manson, Walter C. Willett, Meir J. Stampfer, Frank B. Hu. Fruit and Vegetable Intake and Mortality: Results From 2 Prospective Cohort Studies of US Men and Women and a Meta-Analysis of 26 Cohort Studies. Circulation, 2021; DOI: 10.1161/CIRCULATIONAHA.120.048996
Peris E, Micallef P, Paul A, et al. Antioxidant treatment induces reductive stress associated with mitochondrial dysfunction in adipocytes. J Biol Chem. 2019;294(7):2340-2352. doi:10.1074/jbc.RA118.004253
Dutta S, Sengupta P. Men and mice: Relating their ages. Life Sci. 2016 May 1;152:244-8. doi: 10.1016/j.lfs.2015.10.025. Epub 2015 Oct 24. PMID: 26596563.
Romagnoli C, Marcucci T, Picariello L, Tonelli F, Vincenzini MT, Iantomasi T. Role of N-acetylcysteine and GSH redox system on total and active MMP-2 in intestinal myofibroblasts of Crohn’s disease patients. Int J Colorectal Dis. 2013;28(7):915-924. doi:10.1007/s00384-012-1632-2
Swiderska-Kołacz G, Klusek J, Kołataj A. The effect of melatonin on glutathione and glutathione transferase and glutathione peroxidase activities in the mouse liver and kidney in vivo. Neuro Endocrinol Lett. 2006 Jun;27(3):365-8. PMID: 16816830.
lyosomal acidifiers (only in old ppl) - https://pubs.acs.org/doi/10.1021/acschemneuro.1c00804
valproic acid in c elegans? Valproic acid - is it pro-longevity or anti-longevity? (it helps open up chromatin, which might make it more damage-prone) - Rapamycin News
bromodomain inhibitors?
=> i would not expect huge effect sizes in these, but some of these can be targeted well…
Rejuvenation Science News (RSN)
Dmitry Dzhagarov
Favorites · tpoe6P 1ha:5ag5t0uu3 7yMt iM ·
Can we live longer right now?
https://aging-us.com/new…/altos-labs-quest-for-immortality
In his research perspective, Dr. Blagosklonny writes that potential life-extension with rapamycin may allow us to win time while awaiting future discoveries that will reverse aging.
There are three overlapping groups of drugs for rapamycin-based combinations:
Group 1: A drug (e.g., metformin, aspirin, angiotensin II receptor blockers, and PDE5 inhibitors) that is useful in several age-related diseases and conditions [28].
Group 2: Drugs that can extend lifespan in mice: Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid [29–31].
Group 3: Gerostatics. In cell culture, gerostatics slow down time (figuratively), decelerating both cellular mass growth, cell cycle progression and conversion to senescence, a process known as geroconversion [32, 33]. (Note: gerostatics should not be confused with senolytics [32]). Rapamycin is a prototypic gerostatic [32, 33]. Gerostatics exert static effects on cell proliferation. In nonproliferating cells, gerostatics decelerate geroconversion.
In cell culture, mTOR inhibitors (e.g., rapamycin) may increase cellular reprogramming, potentially by preventing cell senescence [34, 35]. The following gerostatics have been identified in cell culture: nutlin-3a, pan-mTOR inhibitors (such as Torins) and inhibitors of Mek, PI3K and S6K [33]
Bezafibrate - Wikipedia (reduces mitochondrial aging), slowed down the rate of epigenetic aging (Fig. 3d and Extended Data Fig. 6) and extended the proliferative capacity of HDKs (Fig. 3e)
gemfibrozil
A chemical biology approach to identifying molecular pathways associated with aging - PMC
[don’t expedct huge effects but could wstill be worth looking into[
Brian Kennedy says gemfibrozil is uniquely effective among the fibrates. Also TGs are worse than LDL
. In our study, we utilized U-937 cells as a model system to unveil the effect of four selected bioactive compounds (chlorogenic acid, oleuropein, tomatine, and tyrosol) to reduce oxidative stress associated with adduct formation in differentiating cells. The purity of the compounds under study was confirmed by an HPLC analysis
https://www.biorxiv.org/content/10.1101/2022.08.29.505222v1 (one is a tbf-antagonist, the other a tricyclic)
Following an inverse dose-response relationship during AX fiber supplementation was a group of lipids that included PCs, phosphatidylethanolamines (PEs), PE-plasmalogens (PEPs), ceramides (CER), SM, and CEs (Figure S3C; Tables S3D, S3E, and S4A; all lipids FDR < 0.05). PCs and PEs are secreted in lecithin with bile but do not go through enterohepatic circulation to the same degree as bile acids. These lipids are also enriched members of the myelin sheath. Overall, this decrease in lipids demonstrates a generalized hypolipidemic effect of AX. The molecules showing the inverse dose-response correlate together, including the PCs, PEs, CEs, LDL, and total cholesterol (all FDR < 0.05; Figure 3F; Table S3E). Furthermore, these molecules inversely correlate with the secondary bile acids (all correlations FDR < 0.05; Figure 3F; Table S4A).
It seems you fell for Vitamin D hype. Vitamin D is a hormone and it’s not a “more is better” deal.
“Among healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD”
Not to mention, excessive vitamin D (whether due to supplement mislabeling or targets defined as higher than 40 ng/mL) may cause hypercalcemia, hypercalciuria (which is also associated with osteoporosis risk), and kidney stones, and association studies found a modest increase in the risk of specific cancers, mortality, and falls.
Canagliflozin is associated with osteoporosis, bone fracture risk, and decreased bone mineral density.
CALERIE RCT showed those who are CR had low bone mineral density at clinically important sites for fracture risk. The level of IGF-1 is important for bone health. Cortisol may increase with CR which also increases risk. Smaller and weaker muscles = bones experience less force from muscles and become weaker.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834845/
We don’t know if exercise + CR (no malnutrition) may be even worse for bones in humans but it does so in mice which lines up with human data so far.
“We demonstrate here that exercise appears to be harmful to bone during calorie restriction, in congruence with clinical data”
https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.3872
Protein boosts calcium absorption btw. Protein restriction may be even worse. Certain cruciferous vegetables ie Brussel sprouts are supposedly “high in calcium”, but it’s not really that practical. As an example, you need ~10 lbs of Brussels sprouts to get to ~1000 mg of calcium per day. There may be harm from calcium from supplements/fortification due to quick spikes in calcium, but that hasn’t been documented for dietary calcium.
“Non-meat eaters, especially vegans, had higher risks of either total or some site-specific fractures, particularly hip fractures”
How’s your DEXA scan T-score doing recently? Seems like your previous one here was T = -3.0 with a A/G ratio of 0.52 which is associated with low bone mineral density.
You may be at risk for fractures in the long run and many people can die from falling btw. At apparent T=-3.0 you might be at risk of fractures as early as less than age 40.
Not many docs will check men at risk of osteoporosis under age 50 (or if they are old school probably 60s+) due to rarer cases and probably won’t recognize the potential risk factors such as low libido and of Asian descent. Men of Asian descent get missed all the time despite higher risk.
Fragility ain’t longevity. You’re missing muscle-bone cross-talk. If the bones are fragile enough, it can result in early mortality.
Muscle, fat, and bones are all endocrine organs.
Okay thanks for this post - it is helpful. I read it and created an entire thread on rapamycin.news for it.
Lol, this is gonna be my excuse for taking zoledronate, which is an unexpected source of a lot of other longevity benefits…
lol, my diet led to my osteoporosis, but this may be net-good for my longevity because it was THE excuse to put me on zoledronate
Return to post #1: The most promising supplements/drugs/small molecules/geroprotectors for longevity
new additions: psilocybin (N=1 paper), but the % increase is really striking.
retatrutide
