The most promising supplements/small molecules for longevity

The current molecules most likely to work -

MAYBES

BE CAREFUL ABOUT HERBS/SPICES (EVEN GREEN TEA) - HERBS CAN CAUSE LIVER DAMAGE IF CONSUMED IN EXCESS (especially the ones that are very potent). If you use them, make sure to regularly measure liver enzymes

Vitamins/minerals to supplement:

NAD+ is worth looking into but doesn’t boost lifespan. See Brad Stanfield.

Experimental Small Molecules i’m most intrigued by XJB-5-131, deuterated PUFAs, and bendavia/SS-31 (SS-31 more for older than younger people - see Nathan Basisty presentation). There are so few lifespan studies on this (or even just epigenetic age studies on it). Go encourage VitaDAO people to stockpile these for studies!!

DOI is a super-potent anti-inflammatory at low doses

Ones worth knowing about but which may not work:

cross-link breakers like ALT-711 and algebraiem

4 Likes

What Anti Aging Supplements Should I Take? My Top 5 - YouTube (has some good sources!)

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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21h

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)




Koschei the immortal and anti-aging drugs - PubMed
In Slavic folklore, Koschei the Immortal was bony, thin and lean. Was his condition caused by severe calorie restriction (CR)? CR deactivates the target of rapamycin pathway and slows down aging. But…


pubmed.ncbi.nlm.nih.gov




Mikhail Blagosklonny
@Blagosklonny

·

21h

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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21h

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

·

21h

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

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:

  1. 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

  2. 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

  3. 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.

  4. 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

  5. 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 DzhagarovFavorites · 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]