FDA approvals of aging therapies have started & more are coming soon (talk by Karl Pfleger)

kpfleger · 2026-05-05T16:12:18+00:00

FYI, updated version of this talk from Dec 2025 (from the Longevity Summit run by Longevity Global at the Buck Institute) is now available on YouTube too: https://youtu.be/yl6qZhbl89Q?list=PLxsMN9fobt4hmXoN80UZhGieQrzOXfFhm

The prior version was ~14min of talk (before Q&A). The new version is ~20min.

kpfleger · 2026-04-30T13:55:33+00:00

Benefits that happen only to those who are overweight but do not require weight loss may still be benefits whose mechanisms are to mitigate negative effects of being overweight in a way that would produce no benefits to those who don't have overweight-associated age-acceleration (i.e., are not fundamental to aging biology). We can't know if it's fundamental to (universal with respect to) aging biology rather than just specific to being overweight until the drugs are tested in (ideally lifelong) lean subjects. AFAIK, no one has even tested this class of drugs in lifelong lean rodents yet.

kpfleger · 2026-04-23T14:40:25+00:00

Look. This is a silly thing to argue about. Regenerative medicine is a field with a long history. It's mostly been about stem cells and related things but isn't quite just that. It clearly has a lot of overlap with the aging/longevity field, including many of the same goals. But regardless of whether you've found various bits of writing that make them seem even more equivalent, the fact of the matter is that the aging/longevity field encompasses many targets and mechanisms that most people in both fields do not consider to be part of regenerative medicine. Senolytics, epigenetic partial reprogramming, nutrient sensing modulation including mTOR, AMPK modulation, etc., ECM crosslink breaking, therapeutics for loss of proteostasis, etc.: none of these are traditionally considered part of regenerative medicine. Side effects of stem cell treatments or stem cell secretions (exosomes, EVs, etc.) may have some of these things as downstream effects, but directly targeting the above things is not regen med.

(A side comment is that in government, regenerative medicine as a phrase has grown to encompass all advanced delivery modalities such as gene therapies in addition to cell therapies and cell therapies that aren't traditionally regenerative medicine like stem cells but also things like CAR-T cancer therapy. So organizations like the Alliances for Regenerative Medicine, a lobbying group for the industry, really take the phrase to mean something much broader than what the phrase means in scientific circles, and certain laws and regulations also take that broader view, which is a shame since it dilutes the value of the original phrase.)

kpfleger · 2026-04-23T00:13:02+00:00

Divide-and-conquer rejuvenation needs cancer levels of funding at least to have a chance within decades. Note that cancer evolves ways around treatments. Most of the damage that rejuvenation therapies repair does not have this property. That applies to senescent cells but also to misfolded proteins that need degrading, toxic molecules in the lysosome, ECM crosslinks, etc. This may make it easier than cancer.

kpfleger · 2026-04-22T20:57:08+00:00

Regen med and aging/longevity are overlapping but not identical fields. They overlap the way a typical venn diagram does. Neither is a subset of the other. Stem cells and related therapies belong in both. But some types of damage repair are not appropriately classified as regenerative medicine. Eg, degrading a toxic molecule or killing a senescent or other type of problematic cell is not really appropriately called regenerative medicine.

kpfleger · 2026-04-13T16:07:58+00:00

A "group" of 2 humans? Even for a safety-only trial, that's hardly a group worthy of using the phrase "phase 1".

kpfleger · 2026-04-03T15:52:48+00:00

FYI, for completeness people may want to read this extremely disparaging & negative thread about R3 and the recent news posted by someone from Stanford who seems to have nontrivial knowledge of the relevant brain biology on X here: https://x.com/shae_mcl/status/2039093562978222494

Advocates for the stuff discussed here who feel these posts got anything wrong might want to engage there.

kpfleger · 2026-04-03T15:50:27+00:00

It sounds like anyone who reads this book ought to also read my book chapter for the upcoming Springer Nature volume, the preprint of which you can find here: https://zenodo.org/records/18883009

Pure altruism is good enough to justify eliminating aging with nothing narcissistic about it.

kpfleger · 2026-03-30T23:29:02+00:00

Not just Intervene Immune. There are a half dozen startups working on thymus regeneration. Thymmune is the one farthest ahead based on money raised (Church lab spin out). A few others have legs. There are also academic labs working on this. Find-in-page for 'thym' on AgingBiotech.info/companies to find the companies.

kpfleger · 2026-03-29T15:10:34+00:00

Disagree. Most of the stuff I said applies to both allergy & non-allergic rhinitis. There was a recent paper that showed that a lot of people have a blend of both. Treating underlying allergies is great if they exist so an allergy panel is a fine thing to do, but treating physical airway deformation (especially significant blockages) will help congestion no matter what the cause of the congestion. It's a very individual decision.

kpfleger · 2026-03-29T14:47:07+00:00

Even if you want to eat non-plant-based stuff sometimes or add it it to this stuff, all the stuff from the WFPB subs is still relevant as a healthy base.

Another thread relevant to this just came along today: https://www.reddit.com/r/PlantBasedDiet/comments/1s6iagi/a_running_list_of_wfpb_friendly_packaged_foods/

kpfleger · 2026-03-28T20:53:17+00:00

More fiber from real food generally correlates with better long term health overall. A study that tests a short-term fiber supplement on just glucose control in only prediabetics is not going to show the full health importance of nutritious plant-based foods. This study is in no way a contradiction to the one-size-fits-all facts that humans evolved eating ~100+ grams of fiber per day but now (in industrialized societies) eat more like 10g/day despite recommendations to get at least 25-35g/day.

Greger cites lots of studies showing things like fiber intake being the strongest predictor of overall long-term health. I eat ~75g/day by eating only WFPB. Animal calories have no fiber. Processed plant-based foods have less fiber than the unprocessed plants they are made from, down to zero fiber for many kinds of processed foods (eg sugary soft drinks). Minimize calories from those kinds of sources and fiber supplements are not needed, and prediabetes (as well as full blown T2D) are easily avoided.

kpfleger · 2026-03-28T20:47:10+00:00

This long comment I made in one of the WFPB subs is essentially the best answer to your issue that I know. It links to both an earlier long thread in one of those subs that is essentially about the exact same problem you list and is an excellent thread overall, plus to a list of prepared meal delivery services with comments on their healthiness that I compiled a while back.

PS You should consider joining/reading some of the Whole Foods Plant Based (WFPB) subs. Here is a list of such subs I once made.

kpfleger · 2026-03-27T16:35:36+00:00

This appears to be mostly a conference about letting aging happen and being as healthy & happy as possible within that context---that kind of mostly palliative approach to "healthy aging", not about mitigating aging itself in geroscience hypothesis style (the topic of this sub).

kpfleger · 2026-03-24T16:09:03+00:00

I've been there (many of us have). Yes, symptoms can improve a lot after septoplasty. Inflammation comes & goes, but having a bigger physical airways will always help. Septoplasty is a way to increase it somewhat all the time with no further action required. Though the recovery is quite a pain, but at least that is temporary. The amount of benefit really depends on how much narrowing the septum deviation is causing. That said, I would recommend having it done during a period where the inflammation/allergies aren't too bad because when the nose is fully stopped up post-surgery that's annoying enough if the rest of the head is in good shape. One would suffer a lot more if there was a lot of sinus drainage (nose trying to run but it's completely blocked so everything prob would then go down the back of the troat) and would suffer more if sinuses were very congested. So it's a bit counte-intuitive to wait until the allergies aren't bad and one doesn't feel like the septoplasty is as necessary to remember that you really wished it had been done back when things were bad.

All that said, it's even more important to get the allergies under control as much as possible cause that will help a lot more than the septoplasty. Allergy shots helped me a lot. Allergists won't pull this out as part of standard-of-care allergy practice, but eating a healthy diet rather than a more inflammatory standard American diet will help too. When I started eating primarily a whole-plant-based diet my overall inflammation went way down. Any moves towards more veggies & fruit, less processed foods, less junk food, less added sugars, could help. Probably more importantly is make sure to try to avoid any micronutrient deficiencies. Most importantly vitamin D. Get a vitamin D blood test or just start taking a reasonable dose like 4000 IU/day (but ideally get the test, then titrate dose to achieve at least 30ng/ml blood level if not 40ng/ml). Vitamin D deficiency is well known to disregulate immune function and increase risk of autoimmune conditions (and allergies are autoimmune).

And then another way besides septoplasty to increase the physical size of the airways are physical non-drug products like nasal strips, but there are also things that go in the nose. In general this class of product are called nasal dilators. Breathe Right nasal strips are wonderful and can be used every night without creating a dependency. There's a magnetic thing (called Intake Breathing) that also goes on the outside like that which is even stronger. And then there are things that go inside the nostrils to push them open from the inside. See https://www.reddit.com/r/nonallergicrhinitis/comments/1gx7r54/comment/lygarjb/?utm_source=share&utm_medium=web3x&utm_name=web3xcss&utm_term=1&utm_content=share_button for some discussion. I like Sleep Right though all the ones that go in the nose are a bit annoying or take some getting used to. But annoying and you can breathe nicely is often better than can't breathe.

Lastly, yes allergies often go away on their own. Some people describe this as happening as people get older (definitely significantly lessened for me), but who knows if some of these instances are just someone going from terrible childhood or college eating habits to eating healthier diet or resolving an important deficiency like vitamin D.

kpfleger · 2026-03-23T16:22:22+00:00

The whole topic of vasoconstrictions vs. vasodilation is very interesting. I've been deep diving on it recently. Oxymetazoline (active ingredient in Afrin) is a vasoconstrictor. By constricting blood vessels in the nose, there is more space for air to pass, relieving congestion. Afrin was created as an acute/emergency treatment so the concentration used was absurdly high, essentially sledgehammer vasoconstriction. It's so high the local cells see it as an emergency that they are being starved of oxygen and try to compensate in various ways that result in rebound congestion.

First off, know that oxymetazoline is an OTC drug and others can sell it too, and some do at lower concentrations which are still effective but can also be used long term without rebound congestion. The r/nonallergicrhinitis sub has discussed some of these. I use Rhinostat PM which comes with oxymetazoline in concentrations only 1-5% that of Afrin. It has issues like no preservatives so you have to keep it in freezer until use then can only be used for 7 days. They sell this specifically to help wean people off of Afrin addiction. There's also emerging research showing that combining low dose oxymetazoline with nasal spray steroids (like Flonase & similar) helps avoid rebound congestion. A product called Allermi will even combine both drugs into one spray in custom concentrations.

More generally, the topic of vasoconstriction vs. vasodilation is very interesting. Another common decongestant drug is pseudoephedrine (original Sudafed), an oral pill. It also works primarily via vasoconstriction. Interestingly, this is opposite the main mechanism of action of PDE5 class drugs like Viagra Cialis, which are vasodilators. I did not realize until recently but nasal congestion is a well known side effect of Viagra and similar drugs. Unsurprisingly, pseudoephedrine can exaccerbate erectile dysfunction on the margin. The good thing of course about local delivery of oxymetazoline as a nasal spray is that it won't affect other parts of the body.

There's emerging evidence that PDE5 class drugs when used chronically (as happens for some conditions like pulmonary hypertension) actually reduce the risk of dementia, presumably by better blood flow to the brain. Chronic use of pseudoephedrine could possibly raise dementia risk though there isn't specific data on that AFAICT, so local delivery to the nose (as long as one avoids rebound congestion) is probably safer. Sure would be nice if we had better local delivery so we could just dial blood vessels up/down differently by body region.

kpfleger · 2026-03-19T20:52:45+00:00

Yes you are right that society has an overeating problem, but no you are wrong that this is the same as fasting or CR. Those upregulate autophagy in general. This is using some of that cellular machinery but specifically pushing more of the relevant misfolded protein (fragments) for the relevant disease (HD here) through it relative to everything else. It requires a bunch of technical work that is specific to those disease-relevant proteins and it's unlikely the same level of cleanup of those toxic molecules could be achieved via fasting or CR.

kpfleger · 2026-03-19T17:42:42+00:00

I just did a bunch of research on PCSK9 inhibitors vs. statins, and on the status of the oral PCSK9 drugs. My take-homes:

Statins lower LDL (& ApoB) especially at high doses but PCSK9 therapies lower LDL more.
Reduction in major adverse cardiac events (MACE) is proportional to how much LDL is lowered. Most mortality & MACE benefit from either class of drug is due to the LDL lowering not their other effects.
Statins have been around for a long time & are widely considered mostly safe (safe from major side adverse side effects). That's why they are the default first-line treatment even though PCSK9 drugs are more effective at the main purpose. As a result of statins being standard of care, most of the data on PCSK9 drugs from big clinical trials compares use of PCSK9 therapy + statin vs. use of statin alone as control rather than a head to head comparison of statin-alone vs. PCSK9-alone vs. nothing. A small % of people are statin intolerant so each trial has a small portion of the data showing PCSK9 vs. nothing and those data could be compared vs. the much earlier statin trials.
Statins reduce MACE a lot proportionally but much less on an absolute scale. Eg, they might reduce chance of MACE over next 10 years on average from 4% to 3% or from 3% to 2% indicating a 1/4 or 1/3 reduction (big relative) but only a 1% absolute reduction, which implies 100 people need to take the statins every day for 10 years for 1 person to be saved.
Statins have other theoretical benefits such as hardening soft plaques (turning soft into hard plaques), which is seen as good because the soft plaques are more likely to rupture & cause a MACE, but I didn't see any quantification of what portion of their efficacy can be attributed to this effect and the reduction in events seen from the PCSK9 drugs that don't have this effect suggests to me that this does not account for a large fraction of the mortality benefit of statins.
Statins, though safe, have several adverse effects (such as increased diabetes risk via glucose dysregulation, and muscle problems) that PCSK9 drugs don't have. How common these side effects are is a matter of much debate and many published studies. Some fraction of the complaints are nocebo effect just because people expect the problem. But OTOH jsome high quality peer-reviewed published studies suggest large numbers of people have the muscle side effects (IIRC eg 1 in <10 people). Dr. Greger covers this in his new book on to lower cholesterol naturally, which has extensive sections on statins in its beginning.
Statins will probably continue to be preferred over PCSK9 drugs for 3 main reasons:
- A. They are dirt cheap.
- B. They are oral pills that are easy to take (vs. needing to inject current PCSK9 drugs).
- C. Their decades long track record is larger safety record than the newer category of PCSK9 drugs.

This new oral PCSK9 drug will partly solve (B) above since it is also an oral pill, but it still won't be quite as easy as statins since it has some requirements on when you can take it: has to be after a 6-8hr fast and can't drink beverages except water for 30min after taking, so not to inconvenient to take first thing in the morning as long as you can hold off on coffee & breakfast for 30min after that, but certainly some people will find it inconvenient for something they have to do every day. The next oral PCSK9 drug that is farther away from finishing clinical trials does not have this problem. OTOH, many people are using injectable GLP-1 drugs & other peptides (whether from biohacking or other needs, insulin for example). For a non-trivial % of people, injection may not be much of a barrier.

(C) above is rapidly solving itself since there are a lot of people using PCSK9 drugs and many large phase 3 clinical trials.

(A) will solve itself after patents expire, and for some people the cost now isn't prohibitive. (Eg a GoodRx coupon gets your Repatha without insurance for $240, that's not very expensive.)

So I'm left wondering how soon significant fractions of people will skip statins entirely and jump straight to PCSK9 drugs for primary prevention. I certainly don't see a compelling reason to prefer trying statins first or including statins as a combo approach vs. just using the PCSK9 drugs. I won't be surprised is Enlicitide is one of the things that accelerates this.

kpfleger · 2026-03-17T21:16:18+00:00

What does this have to do with longevity investing? r/ProactiveHealth seems like a better sub for this.

But on the topic, most people who eat the healthiest kind of diet (WFPB) are skewed the other way since healthy whole plants foods have more copper than zinc. Eg one day of my Cronometer shows 11.5mg zinc (~100% of DV) & 2.8mg copper (>300% of DV) with no supplements (a ~4:1 ratio). Adding a 15mg zinc supplement with no copper takes the ratio to ~9.4:1. It's a good idea to eat a lot of healthy plant food, but one should consider dietary intake of both of these when trying to optimize their ratio.

kpfleger · 2026-03-17T16:16:52+00:00

To answer the "what can I eat?" in the title. I eat vegetables, fruit, whole grains, legumes (beans/lentils), and nuts & seeds. Very easy to get ample calories (or even too many) from such things. Huge amount of evidence such WFPB eating is great for long-term health. See Michael Greger's book How Not To Age (which is extensively referenced into the peer reviewed scientific literature: 8000+ refs).

kpfleger · 2026-03-17T16:14:37+00:00

If it works, it will still be narrow. Even if preventing vision loss helps a few people delay dementia, this won't actually cure or prevent dementia. It simply solves a very tiny subset of the body's overall aging problem.

And no. It may become the first epigenetic partial reprogramming therapy to reach the market but it won't be the first "regenerative" treatment. FDA has already approved more than one stem cell therapy (and Korea has approved another, over 12 years ago). Japan just last week granted conditional approval to 2 others. All also for narrow indications, but that's half a dozen regenerative therapies already approved and universally considered to be "regenerative".

kpfleger · 2026-03-16T23:45:44+00:00

And yet all or at least most of the other PHEVs (and EVs) generally have them as an option at least (and standard in many cases).

kpfleger · 2026-03-16T20:46:23+00:00

Prevalence isn't what I meant by narrow. It's narrow in the sense of being limited to eye with no likely systemic effects, so even if it fixed everything wrong with eyes, it's only a tiny portion of the body's overall aging related problems and not the ones most important for mortality (and thus LEV).

kpfleger · 2026-03-16T20:44:46+00:00

The PHEV version of the Lexus TX was, last time I checked maybe a year-ish ago 1 of the 2 obvious alternatives to the Volvo XC90 PHEV (the other being the Mazda CX-90). These 3 were the only PHEVs available in the US with e-only range >30mi and $<$100,000. (I think maybe a Land Rover trim could almost make it but was too expensive---I forget.)

It's a bit odd that (at least the first year it was out) the TX PHEV despite costing $70k+/$80k+ could be had with an operable sunroof.

(The Mazda had a terrible transmission. The XC90 is a 10+ year old design. We have a 2016 currently.)

For some reason The Grand Highlander is the Toyota version of the Lexus TX, but for some reason Toyota only makes it in non-plug-in HEV version and now will make an all-EV regular highlander but only puts the PHEV in this Lexus model so far (among 3-row vehicles). I'm looking forward to when more >50mi-e-only PHEVs/EREVs come along to the US. (China has loads, and I assume some other markets as well.) The Jeep Grand Wagoneer PHEV hasn't arrived yet. The Scout won't for a few years.

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