Thread 76526512

Sup /fit/, Bryan Johnson's small molecule skill issues finally caught up to him in the form of some rando influencer who also has small molecule skill issues finally beating his biomarkers.

Meanwhile, we've got Chinese researchers dropping senolytic papers where a bunch of classically oncology-targeted protein pathways are being repurposed into osteoporosis research:
>The Role of Senolytics in Osteoporosis
>https://www.mdpi.com/2218-273X/15/8/1176
>We discussed major types of senolytics, such as natural compounds, kinase inhibitors, Bcl-2 family inhibitors, inhibitors of the mouse double minute 2/p53 interaction, heat shock protein 90 inhibitors, p53-binding inhibitors, and histone deacetylase inhibitors. This review also highlights the progress of senolytics in clinical trials. However, clinical results diverge from preclinical evidence. Therefore, senolytics should be critically evaluated as a potential therapeutic strategy for osteoporosis, with further validation required.

Of course, there is a lot more to proteome modulation than just senolytics or Yamanaka factors. Anyone else more advanced than DWS and Bryan Johnson looking at specific protein targets to delay/prevent age-related disease?

>The higher the daily protein intake of middle-aged and older individuals, the lower the risk of developing osteoporosis
eat borger?

>>76526887
If you do a deep dive on advance glycation endproducts, steakburgers cooked with acid marinades are better from an anti-aging perspective. But the whole "durr avoid meat" shit is kind of a meme as the Jared guy proves. He's probably even cooking skill issues, just avoid much ultra-processed meat.

>KAT8 Knockdown Reverses hucMSC Senescence and Enhances Diabetic Wound Healing Efficacy
>https://pubmed.ncbi.nlm.nih.gov/40816295/

>Lentinan rewrites extracellular matrix homeostasis by activating mitophagy via mTOR/PINK1/Parkin pathway in cartilage to alleviating osteoarthritis
>https://www.sciencedirect.com/science/article/abs/pii/S0141813025074574

>>76526512 (OP)
Got anything for grey hairs?

Can I get a schizo opinion on my plan to start taking Deca?

"To convert a rat dose (mg/kg) to a human equivalent dose (mg/kg), you would divide the rat dose by 7.4."

20mg/kg/wk divided by 7.4 = 2.7mg/kg/wk My dose - ~81kg x 2.7 = 218.7
https://www.sciencedirect.com/science/article/abs/pii/S0024320518304181

"Cardiac collagen deposition was increased in the NDL group, with this effect being attenuated by enalapril (ACE inhibitor) in NDL-E animals"

Amla acts as a non-drug ACE inhibitor

Deca is shown to increase oxidative stress

Hypothesis - A much-reduced dose of Deca relative to the above study, coinciding with high-dose Amla supplementation and poly-antioxidant use plus low inflammation diet should completely counter the cardiac remodeling and blood vessel hardening effects of Deca

>>76526512 (OP)
Hey there pharma anon (mwah)
Is there anything more promising than mTOR inhibitors + histone deacetylase inhibitors + AMPK agonists? (Intentionally left out anything potentially oncogenic)
Am I still a boomer in senescence research?

>>76530382
copper+manganese supplements, topical olive oil.

>>76530496
The only way to know for sure is probably to do it and run a bunch of cardiac testing, but it seems like a decent hypothesis. Ecdysterone and black cumin have both recently had a lot of cardioprotection evidence too.

>>76530927
GAS6, PAI-1 and IL-11 inhibitors/downregulators are all starting to look pretty attractive in addition, but there are a really lot of other potential mechanistic targets dropping all the time.
>Reversible ALKBH5 cytosolic aggregation accelerates cellular senescence
>https://www.nature.com/articles/s41418-025-01560-1
>Herein, we show the reversible ALKBH5 aggregation in cytoplasm promotes cellular senescence. Mechanically, ALKBH5 aggregation causes cytosolic retention, resulting in the m6A dysregulation and m6A hypermethylation of Cdk2, which promotes Cdk2 RNA instability to drive senescence.
>Forced nuclear entry by NLS-ALKBH5 can prevent senescence in vitro and in vivo.

>>76530382
Here are the real schizo-tier *potential* interventions: https://scholar.google.com/scholar?cluster=7685501269275675234

Problem with a lot of them is they are also associated with hair greying as a potential side effect and other problems if used systemically, it's a bit of a poorly studied crapshoot.

Pharma anaon, what should I add to my stack for maximum longevity?
Finasteride 1mg/day
Astaxanthin 15mg/day
Empagliflozin 2.5mg/day
Ezetemibe 5mg/day
Rosuvastatin 5mg/day
Tadalafil 2.5mg/day

>>76531014
>copper+manganese supplements, topical olive oil.
i'm going to try that. thanks.

>>76531074
Half of that is prescription only - how are you getting it?

>>76531188
Prescription from dermatologist cardiologist and family doctor.

>>76531223
They sound like real boomers. I would have guessed their ultimate longevity strat was just fish oil, aspirin, vitamin D, and metformin, kek.
>protip: check out the supplement stacks of the rejuvenation olympics leaderboard people where you can find 'em

>>76531261
They are just rich and let others decide for them without actually researching anything themselves. I base my stack solely based on ITP for now as they have the most rigorous animal testing and some aesthetic anti aging such as finasteride. Supplements simply have too small of an effect to be worth the money.

>>76531223
Why would a derm prescribe any of them? I guess a cardio might give ezetemibe and the statin but not without you having a medical condition to warrant it.

>>76531014
>but there are a really lot of other potential mechanistic targets dropping all the time
Downstream stuff doesn't seem as worthwhile to target, no? One because you'd need a cocktail of drugs and two because theories of crosstalk are largely in their infancy

>>76531074
I would strongly suggest 17a-estradiol in place of finasteride
Why not take a GLP-1a over empagliflozin?

>>76531261
Where do I find these stacks? I'm not into supplement communities

>>76532424
>Downstream stuff doesn't seem as worthwhile to target, no? One because you'd need a cocktail of drugs and two because theories of crosstalk are largely in their infancy
It's kind of variable.Like, hitting targets way downstream of mTOR or 5-AR for example are 100% worth it. Sometimes the crosstalk properties of a protein are fairly clear, other times it's not so clear. Some targets you can get by with just one drug to modulate it, others do need a cocktail sometimes to manage the activity of ancillary pathways or get enough activity. There aren't any great generalizations there.

>Where do I find these stacks? I'm not into supplement communities
Look up the people on...
>https://www.rejuvenationolympics.com/dunedin-pace

Waah-waah wee-waah, the land of Gypsy and Vampires brings us a hit on an interleukin-8 knockdown plant...
>The Effects of Anthyllis vulneraria Hydroalcoholic Leaf Extract as an Adjuvant in Wound Healing
>https://www.mdpi.com/2076-3417/15/15/8388
>IL-8 levels decreased after the extract treatment, while no significant microscopic changes were observed.

>>76533007
>wound healing
lurking these threads feel like
eavesdropping on a bunch of white mages

>>76533007
Still need to figure out what interleukins actually do

>>76532424
I can't reliably source 17a-estradiol, all sources I have found are expensive including commercially available alfatradiol from Germany. SGLT2i are cheaper than GLP-1 drugs, have direct ITP research and clinical outcome data in terms of organ fibrosis and CV benefits.

>>76531036
lamivudine... the HIV drug? maybe that PrEP thread was right about epstein-barr

>>76531074
swap out fin for duta, fin is really shit for you because it fucks up the levels of steroids downstream from the pathway since it only inhibits types 2/3 of 5AR, duta inhibits them all equally so its way better because it won't break some rate limiting step of some nigh unheard of steroid that is produced 5 enzymes down the line from all the reductase activity being shunted into type 1 5AR
use topical tretinoin, 0.05% is good, but start lower so your skin gets used to it let it slough off into a chemical burn, apply at night before bed and wash it off in the morning, use loads of sunscreen
add 10000IU of vitamin D daily
personally I don't like rosuvastatin much because the sides are not worth it, I'd go for pioglitazone over it any day, PPAR gamma agonists are fire for lowering cholesterol and keeping insulin and your metabolism in tip top shape, if you ever get high blood pressure opt for telmisartan.
the rosuvastatin you're taking comes with the ezetimibe right? in that case discontinue both because ezetimibe has loads of drug interactions, honestly not worth the hassle of checking every time, also it stops your intestines from absorbing vitamin K, get some super K from life extension (brand doesn't matter desu but this one is the one i use since its pretty complete) and take it once a day
take vitamin C, take NAC with zinc and copper (the antioxidant activity is very worth it imo)
t.pharmacist anon

>>76531014
>manganese
a lot of people don't even know that stuff is

>>76533724
Buy it from China
>SGLT2i are cheaper than GLP-1 drugs, have direct ITP research and clinical outcome data
Interesting, I would think GLP-1a is better because it acts more upstream (preventing your blood sugar from rising in the first place) which could maybe mitigate other issues

>>76533796
Fin is cheaper and a smaller molecule reliably crossing BBB unlike duta despite the in vitro studies regarding AR type affinity and less potency than duta I still think it has the best results to price ratio. Not going to to use tretinoin or the newer gen retinoids as they don't reach the dermis and you can achieve the same level of epidermal rejuvenation with quarterly TCA or other chemical peels.
Already 2SD above average in vitD levels with 2k IUs per day and not willing to overdose. Ezetemibe has no major interaction and the moderate interaction are mostly mechanism related, already taking vit K separately and have normal coagulation panel. Sorry not going to use PPARG drug over rosuvastatin, none of the statins have ever been removed from the market due to crazy side effects unlike PPARG agonists, and blocking a single enzyme, which the hydrophillic and liver specific low dose rosuvastatin does better than any other statin, makes much more sense than changing protein transcription levels on a systemic level in terms of antiaging.
Not going to chelate all my metals with NAC when astaxanthin exists as an antiinflammatory agent and already have enough cystein in my diet to keep the glutathione in check.

>>76533907
SGLT2i are only slightly worse than GLP-1s in terms of dampening post meal glucose spikes. But GLP-1as have been shown to increase resting heart rate through direct stimulation of SA node which goes against longevity and probably increase atrial fibrillation risk later in life, we can't know for sure we have to wait some decades. They are great for appetite suppression and not much else honestly.

>>76533951
Thanks for the info anon
>>76533919
Isn't there some stuff out there about how DHT might be implicated in neural function? I'm not going to bother with 5a-ri until I can find a topical or tissue-selective one that doesn't cross BBB

>>76534050
You're welcome.
Fin crosses BBB but has low affinity for the 5AR type predominantly found in CNS, duta has higher affinity for that enzyme but does not cross the BBB reliably and is more potent than fin generally. Both are safe options that have been used clinically for a long time and the data regarding neuropsych side effects are so laughably bad quality I was surprised they were actually published.

>>76533919
>Not going to to use tretinoin or the newer gen retinoids as they don't reach the dermis and you can achieve the same level of epidermal rejuvenation with quarterly TCA or other chemical peels.
Newer-gen retinoids are getting pretty good anti-aging evidence, but chemical peels are very under-rated for hair, especially enzyme peels plus immunomodulation of chemokines when you wanna get really experimental past the literature. Bryan Johnson has awful peel skills.

>Not going to chelate all my metals with NAC when astaxanthin exists as an antiinflammatory agent and already have enough cystein in my diet to keep the glutathione in check.
If you have better metals skills than Bryan Johnson, chelating your metals with autism pills is not a bad Faustian bargain. I shoot for 200-300% RDA on micros and they always come back in range on 1,200mg NAC. Bryan Johnson weirdly never tests his micros.

>>76534188
For skin a tretinoin peel every 3-4 months is easier than nightly application and gives the same results.
The androgenic alopecia is solved with finasteride and for the non androgenic causes I might just get a transplant in a few decades just not to micromanage 50 different treatments. Micromanaging every micro is impossible especially metals and electrolytes since the serum levels don't accurately represent whole body levels. If I were to deal with the headache of every single micro I would start with minoxidil since there is some data regarding elastin upregulation and maybe NAC in some decades once I am very old.

Thoughts on EGF pathways? I saw a product in the store recently that said "backed by research" and it turns out that the active ingredient did have some EGF activity, so it makes sense that it would do what it says (make your skin look younger)
Unfortunately don't remember the name of the product but there's probably only a few brands out there anyways

>>76534292
Here is a review discussing some of the evidence for skin use...
>The use of epidermal growth factor in dermatological practice
>https://pmc.ncbi.nlm.nih.gov/articles/PMC10333026/

In terms of hair though, it looks less promising...
>More is Not Always Better in Hair Growth Factors. Epidermal Growth Factor: Hair Growth Factor Involved in Alopecia Areata Pathogenesis
>https://pmc.ncbi.nlm.nih.gov/articles/PMC7759056/
>The mean serum EGF was statistically significantly higher in patients than of controls (P < 0.0003).

Any sort of systemic therapy, the main concern would be potentially increasing the spread of non-small cell lung cancer if you happen to have that at the time. EGFR inhibitors are common therapies for that. EGF is a mitogen but also a cellular differentiator. Topical skin use would probably be the lowest risk

So in terms of stuff Bryan Johnson *is* taking, fisetin may be having more of an impact on his hair than he gives it credit for...
>Senolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12
>https://www.biorxiv.org/content/10.1101/2025.08.13.670216v1.abstract
Topical strawberry extract *probably* grows hair.

>Alpha-Ketoisocaproate Attenuates Muscle Atrophy in Cancer Cachexia Models
>https://onlinelibrary.wiley.com/doi/full/10.1002/jcsm.70044
>KIC suppressed mRNA expression of myostatin, a key regulator of muscle atrophy, more effectively than did l-leucine (−26.37±4.11%, p<0.01). KIC enhanced protein turnover in C2C12 myotubes and maintained 50% cell viability at high concentrations (KIC: 4.68mM, HMB: 3.11mM).

bump

>>76526887
More like make a 60g whey shake

>>76533919
oh well, its your choice then, you asked for an opinion, i gave you one, what about the classic then, some sirolimus, and if you can get it try out a single dose of resminostat every once in a while

>>76536713
>the classic then, some sirolimus
Too broad-spectrum of an immunosuppressant, it's better to start selectively knocking down inflammatory interleukins/chemokines. Good mineral skills can offset the infection risk from sirolimus, though.

keep shilling dude someone will sub to your channel one day
very high effort oc there too bud

>An energy metabolism-engaged nanomedicine maintains mitochondrial homeostasis to alleviate cellular ageing
>https://www.nature.com/articles/s41565-025-01972-7

>Ellagic Acid Mediates the Delay of Dermal Fibroblast Senescence via CSNK2A1
>https://www.tandfonline.com/doi/full/10.2147/CCID.S523963
>EA upregulated CSNK2A1, decreased β-galactosidase activity, restored cell viability and cycle progression, and reduced apoptosis.

>"so, what does it do?"
"oh it's a pill that makes you young again"
>"wow. that's incredible. how much does it cost?
"it's like $1.5 million/year"
>"that's great, totally worth it."
"yeah"

we'll get there. but until then, i'd like to contribute to this thread. did you know that you can remove stains from your teeth by brushing with just ordinary baking soda? it removes all kinds of stuff, like discoloration from smoking and coffee stains. the path to strong and healthy teeth is just eating right and getting proper nutrition.

>>76539058
>ordinary baking soda? it removes all kinds of stuff
but not as much as singlet oxygen, kek.
>t. high-level oxidizer wizard

is there anything here that an individual can actually procure and test as a N=1 study without significant risk of cancer or permanent damage

>>76540092
Yeah, turns out a ton of these anti-aging pathways are modulated by regular-ass foods/supplements. You can actually find a lot of them that seem to reduce cancer risk, but turmeric, NAC, sulforaphane and bromelain are getting some of the most attention recently.

>>76540513
I wouldn't say "regular ass" when its purified to 100x or 1000x
We also have growth hormone, which is made trough biotech research magic now, instead of being cadaver harvested.

>>76540513
Turmeric and NAC have already been on my radar for a while
The other stuff that's extremely purified seems a bit more dicey though, ecdysterone seems to be the only one actually worth the struggle of acquiring

Why the fuck would I listen to what science dorks have to say when they look like this

>>76540714
Most scientists just have low-tier science skills, especially outside their sub-field. He probably trusted le FDA and did fin for his hair, never heard of the CXCL12 signaling pathway except in some cancer paper he skimmed the abstract of in med school years ago.

>>76526512 (OP)
>MDPI paper
based non-science person

To be honest, as an academic (specifically in mitochondrial metabolism), only supps you should take are omega 3s, creatine, magnesium, vit D (no need for K2 if you eat whole food), and B12, and then if veg iodine.

The real longevity maxer is doing an hour of cardio a day and lots of weights.

too many nerds on /fit/ these days

>>76541566
>>76542188
lol not reading MDPI papers when supplements beat boomer pharmaceuticals...
>Effect of Spirulina platensis Versus Simvastatin on the Skeletal Muscles of Experimentally Induced Dyslipidemia: A Multitarget Approach to Muscle Ultrastructural and Cytomolecular Modulation
>https://www.mdpi.com/2076-3271/13/3/137
>Results: Spirulina platensis significantly improved lipid parameters, reduced CK and MDA levels, preserved muscle histoarchitecture, and downregulated fibrotic (TGF-β1) and apoptotic (Bcl2) responses compared to the dyslipidemic and simvastatin-treated groups.

>>76526512 (OP)
why is anyone researching how to fix pathology-related conditions in cases that are entirely preventable in the first place?

why do we need to learn how to optimize the epigenetics of a 130kg pig who cannot stop shoveling glucose into his stomach and cannot go outside to walk or lift weights?

I say the first step towards better health starts in increasing the population among physically active, well fed and well rested individuals by promoting better lifestyle. Medicine was created to prolong life in spite of the environment. A couple hundred years ago that meant bacteria, viruses, parasites and psychological and physiological disturbances. Now it's all about maximizing the lifespan of working stock people so they can live longer with their circulatory disease by taking statins, hypotensigenic drugs and mood regulators since their body and brain are degenerating from lack of anything genuinely stimulating and growth inducing.

Absolutely insane if you ask me.

>>76541566
you forgot testoterone enanthate

>>76544595
Diet, exercise, and lifestyle are first-line things that need not even be mentioned
This entire general is about things you can do on top of that, since even the most healthy and fit people tend to die from "aging"

>>76544595
>>76544650
Especially with muscle-related issues, using therapies off-label in healthy people can give you big performance gains. Classic example would be shit like HMB, it's prescribed in cancer/AIDs patients but also used as a supplement in advanced legal sports doping lmao.

>>76544733
>HMB
lol doesn't do anything if you are eating sufficient protein, even in elderly people

>>76544795
>Effect of β-hydroxy-β-methylbutyrate (HMB) on the Muscle Strength in the Elderly Population: A Meta-Analysis
>https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2022.914866/full
>International society of sports nutrition position stand: β-hydroxy-β-methylbutyrate (HMB)
>https://www.tandfonline.com/doi/full/10.1080/15502783.2024.2434734#abstract

>>76544733
>>76544795
>>76545070
>HMB
How the fuck does this thing work? Nobody seems to have a proper pharmacological explanation

>>76545070
>sufficient protein
>Combining HMB with isomaltulose and whey protein improved power and recovery from intense resistance exercise compared to whey protein alone [Citation 181].
>Kreider et al. [Citation19] administered a fortified protein/carbohydrate supplement with additional 0, 3, or 6g/d HMB-Ca to resistance trained athletes for 28days but showed no effect on body composition or strength. No differences between HMB-Ca, whey protein, or the combination of both were observed when examining exercise-induced declines in strength and markers of muscle damage [Citation 182].
>Furthermore, Jakubowski et al. [Citation 111] compared the effects of HMB-Ca compared to leucine when added to whey protein during a 12-week phased resistance program and concluded that HMB-Ca added to whey protein did not show greater improvement in muscle mass or strength compared to leucine added to whey protein. However, the study was not placebo controlled.
>anon searches PubMed and doesn't even read the basic content of the paper
>2 out of 3 sources cited in the review indicate HMB does nothing when protein is already supplemented
>anon is a retard or works at his local GNC, possibly both

>>76544650
what's the best diet for not dying?

>>76545888
Probably some variant of the Mediterranean diet

Some new info just dropped on what proteins make cows swole...
>Genome-wide identification and characterization of the ubiquitin-specific protease (USP) gene family in cattle: primary analysis of muscle-specific USP genes and their influence on myogenesis
>https://pmc.ncbi.nlm.nih.gov/articles/PMC12362952/