The most promising supplements/drugs/small molecules/geroprotectors for longevity

akc-important-threads
#1

The current molecules most likely to work

Other Lists: ( ITP Test Results Thread | Diabetes and Glucose Control - Life Extension ). Note that mice die disproportionately of cancer, which biases ITP results (and may make some pro-survival/anti-dementia factors have weaker effects than they would in humans)

(the more supplements you take, the higher your chances of taking at least one that suppress your appetite by ~10-15% which alone induces metabolic benefits. Bryan Johnson has a good list). But increases risks of heavy metal contamination and bad synergies (semaglutide reduces need for half of them)

I want to be comprehensive in this post (cover as much as I can) so my post here is long, but the effect size of rapamycin+acarbose+canagliflozin is so so so SO much higher than any of the others listed here that a 90/10 would just involve those two and skipping the rest.

  • GLP-1 agonists like Semaglutide. New Antiobesity Drugs Help People Shed Dozens of Pounds, but They Must Be Taken for a Lifetime | Scientific American Appetite suppressant. increases insulin (which you can reduce by rapamycin). Can induce fasting/calorie restriction/once-a-day feeding (tho hunger mediates SOME of the benefit of CR - https://www.cell.com/cell-reports/fulltext/S2211-1247(22)00608-8 ). Operates on ghrelin rather than leptin (safer this way b/c leptin induces ROS/tolerance). Stronger appetite suppression effects than anything else, may be good for losing visceral abdominal fat. You do not need to consistently be on it (people on trials regain much of their weight after stopping, but for those using it to reduce calories, the reduction in lifetime-integrated calorie consumption still holds). Intermittent (oral) Rybelsus / Semaglutide use in healthy individuals? - #26 by drsteve7777 - Rapamycin Longevity News . Decreases hemoglobin A1C more drastically than other drugs. Not ITP-tested b/c they need to figure out dosing. People often comment on how doing 2-4 day fasts (each month or several times a year) induces long-lasting metabolic shifts - this is the easiest way to do it even if you only do on occasion.Tirzepatide may be even better (though not on a mg-mg/price basis) and is a GIP agonist so it could strengthen osteoclasts. Then there is LY3437943. The doses needed for calorie reduction are smaller than those used in weight loss, so 0.5mg injections work. This is also the easiest way to decrease exposure to microplastics. Overall, I estimate the pro-longevity effect size of semaglutide to be higher than any other drug, including rapamycin. It also reduces the amount of other drugs you have to take due to overlapping mechanisms (I would still take taurine and plasmalogens)

https://www.nature.com/articles/d41586-024-00118-4 - may even act on inflammation independently of appetite reduction

Steve Austad bets on Ozempic + GH for the X-Prize


(lift weights at least once a week to prevent reductions in muscle size, or take breaks in case body fat percentage goes too low)

Daily dosing may be better than weekly dosing for preventing “rebound effects”. Higher doses may increase GlycanAge (small N)

CBD might also increase rapamycin levels.

Rapamycin may induce insulin resistance (https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3384435/ ) and increase blood lipids (esp free fatty acids) and may work better if you transition to high-fat/low-carb or take metformin to reduce these increases. Rapamycin may increase LDL levels (you can suppress with NEXLIZET) and gluconeogenesis (you can suppress with metformin).

There are alternative mTOR inhibitors in research like pan-mTOR inhibitors (eg Dr. Joan Mannick — mTOR’s Role in Aging - Rapamycin Longevity News ) or the mTOR catalytic inhibitors that may be more effective than the rapalogs or allosteric inhibitors (they may also have no mTORC2 inhibition). Considering Pan-mTOR Inhibitors as Alternatives to Rapamycin – Fight Aging! . #118 - Lloyd Klickstein, M.D., Ph.D.: Rapamycin, mTOR inhibition, and the biology of aging - Peter Attia lists RTB101

Miglitol may be even better and is systematically absorbed. Miglitol activates UCP1 - HOWEVER - miglitol may inhibit GIP and weaken the bones. Voglibose is another one

Canagliflozin also works as a senolytic (2024 paper even says its senolytic effects may be better than its anti-glycemic ones)

It may be a good idea to take breaks/take it “1/3” of the time b/c SGLT2 inhibitors can increase appetite/fatigue if taken for too long.

Sotagliflozin is the newest SGLT1+SGLT2 inhibitor and may be better than any of them (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659196/ => also shows canagliflozin is preferred due to SGLT1 inhibition)

canagliflozin is much more effective at reducing postprandial glucose spikes in healthy volunteers than dapagliflozin - though dapafliglozin is still much cheaper and still makes one pee out enough glucose.

  • taurine. Anti-glycative agent. Even Martin Borsch Jensen called the June 2023 paper impressive. Pyridoxamine is also the most interesting understudied B6 vitamer and may reduce ghrelin increases from AGE consumption


  • Nexlizet (bempedoic acid and ezetimibe) to reduce LDL (reduces alzheimer’s risk). Much safer than the statins (which interfere with geranylgeraniol pathway). The proteoglycans in the blood vessel walls of humans seem particularly prone to blood vessel damage, and taking out the primary causes of death in humans does a lot in practice even though LDL in theory doesn’t directly increase aging rate (as you can see in lucky people like Mahathir Mohamad) and there are SOME positive correlations between moderately high LDL and longevity at the population level (even though people with genetically low LDL seem to suffer from no issues, which is the strongest argument for Nexlizet and PCSK9i)

The “weak effects” may also be the result of “too low” dosing (though was the dosing used in ITP much higher than seen in humans?) “Significant dose‐dependent improvement in daily profiles of blood glucose was observed with metformin dosages up to 1,500 mg/day, with a trend towards further improvement observed at 2,250 mg/day” => there were very few humans on the highest dose, and (given the huge differences in relative blood concentrations of metformin seen between mice and humans) it’s likely that the ideal dose of metformin is higher than 2250 mg/day. Mice die disproportionately of cancer, and many cytoprotective mechanisms also protect cancer cells (ESPECIALLY if only started later in life). Pairing metformin with 14ppm rapamycin produced the highest longevity benefits of all interventions in ITP.

It can be a mild mitochondrial complex I inhibitor, which is my strongest concern (but does it do it at low doses, and does mild inhibition of complex I reduce mitochondrial ROS?) And - how does CR affect complex I? I will find out later.

metformin increases GDF15 which can reduce appetite AND associated with frailty (GDF15 is a weird hormone that seems to “stick out” in fraility assays).

Bryan Johnson of blueprint combines metformin with rapamycin with acarbose (he does not yet try the -flozins AFAIK)

A recent metformin study casts doubts on longevity indications => still on metformin monotherapy only (without concurrent rapamycin)

Also, indole-based melatonin analogues

Glycine is in fact an acceptor for methyl groups, and can in that way clear an excess of methionine. Too much methionine is not healthy: methionine is converted into homocysteine, a substance that has been associated with accelerated aging and aging-related disorders (R). Glycine can reduce methionine levels in the blood.

Astaxanthin has shown a variety of clinical benefits with good tolerability and safety. In double-blind, randomized controlled trials, it reduced oxidative stress by 5 mg or 20 mg/day in obese and overweight subjects and 5 mg, 20 mg or 40 mg/day in smokers [11, 12]. The results showed that oxidative DNA damage was inhibited, C-reactive protein and other inflammatory biomarkers were decreased, and tuberculin skin test immunity was enhanced [13, 14]. In another trial, daily astaxanthin doses of 6, 12, or 18 mg decreased triglycerides and increased HDL cholesterol and improved blood flow in microcirculation models

MORE INTERESTING MAYBES

LESS INTERESTING MAYBES

  • atorvastatin [the only statin] - https://www.rapamycin.news/t/first-report-from-epiterna-on-the-search-for-drugs-that-can-extend-human-lifespan/12651
  • estriol and estrone (among estrogens)
  • omega-3’s like https://www.amazon.com/dp/B08F8K36RP?psc=1&smid=A3IQGL03Z0MNP5&ref_=chk_typ_imgToDp . Negative on ITP (but they probably improve healthspan and mindspan way more, and massively boost the average if not the maximum). Omega-3’s are also very easily oxidized, and animals with a higher % of omega-3-based lipids die younger (the relationship may not be everywhere monotonic)
  • creatine (for vegans). May reduce homocysteine levels. Much of the body’s methylation enzymes are used to synthesize creatine, which prevents these methyl groups from reducing homocysteine + maintaining healthy DNA methylation (methyl donors help decrease DNAm age on sum)
  • 4-phenylbutyrate
  • quercetin + datasinib. Senolytics have larger effect sizes in the young (from what one person told me), and Morgan Levine is doing a trial to see their effect on epigenetic aging.
  • ergothionine (in mushrooms). Mushrooms HELLA REDUCE the risk of cognitive decline. cell has a SPECIAL transporter for it, can be stored for ~1 month. https://archive.ph/oiwm2 . lustgarten says too high consumption can increase mortality (U shaped association). found most in oyster mushrooms
  • GLYLO - https://www.biorxiv.org/content/10.1101/2022.08.10.503411v1 (even decreases appetite). The ingredients are so common and GLYLO is way more $$ than justified
  • carvedilol (beta-blockers have risks, but are still net-positive sum and carvedilol has fewest metabolic effects - https://www.sciencedirect.com/science/article/pii/S0019483216000043 ). May be especially important if you take stimulants.

26The beneficial effects of carvedilol compared to metoprolol and atenolol on lipid parameters has been demonstrated in several small studies.13,25,27Carvedilol has selective α -1-adrenoreceptor blocking activity, causing vasodilation and a reduction in insulin resistance

EARLY INTERVENTION MAY BE IMPORTANT THAN LATE INTERVENTION:

Taken together, the data presented here suggest that intervention with AAV-Kl may be more effective in slowing the progression of sarcopenia at an earlier timepoint, rather than rescuing advanced pathology, at which time the transcriptomic response to intervention appears to be more stochastic. An interesting area of future investigation includes the determination of whether network entropy and PPI network architecture may be predictive of the efficacy of therapies designed to counteract the effect of time on skeletal muscle health and function. As an extension of this work, it would also be interesting in future studies to determine whether upregulation of Klotho at a younger age could attenuate functional declines into old, and possibly even oldest-old, age

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 and get heavy metal testing b/c herbs are often contaminated with lead/cadmium

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!! YOU WANT TO PRESERVE CARDIOLIPIN STRUCTURE WITH AGE

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. They may work better if administered earlier, just like the anti-beta-amyloid antibodies

4 Likes
Guide to Living Longer (Alex K. Chen)
THE INDEX of Alex K. Chen aging content
#2

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

#3

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

#4

increase zinc to copper ratio AND magnesium to calcium ratio

#5

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.

#6
#7




Mikhail Blagosklonny
@Blagosklonny

·

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

·

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

#8

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

#9

https://www.youtube.com/c/DrBradStanfield has A LOT (way more conservative/conscientious than I am tho)

#10

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 ÎČ3-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-KoƂacz G, Klusek J, KoƂataj 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.

#11

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


URLs on my deep dives into both p53 and proteasomes last night
URLs on my deep dives into both p53 and proteasomes last night
#12

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]

#13

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)

#14

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).

WOW. PEs + plasmalogens are depleted by dietary fiber (in the same way fiber depletes cholesterol)

#15

Calcium channel blockers https://youtu.be/eLnAEIMUCu0

#16

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.

https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-label-diabetes-drug-canagliflozin-invokana-invokamet

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.

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(The association between body fat distribution and bone mineral density: evidence from the US population | BMC Endocrine Disorders | Full Text)

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.

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Muscle, fat, and bones are all endocrine organs.

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#17

Okay thanks for this post - it is helpful. I read it and created an entire thread on rapamycin.news for it.

#18

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

#19

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1 Like
#20

Return to post #1: The most promising supplements/drugs/small molecules/geroprotectors for longevity