#1

Last year during the ARDD 2024 conference the researcher Nir Barzilai presented an updated version of a ranked list of compounds with longevity potential. One purpose of the list is to help to guide the research efforts and financial investments in the field. One thing to keep in mind is that even if these compounds have longevity potential they will never as single interventions result in any radical life extension. Maybe they can give an extra decade or two in life extension. But regardless of that I think there is a benefit in trying to push the research forward around some of these promising compounds.

According to Barzilai’s paper he proposes that the four top compounds that the field should focus on are SGLT2 inhibitors, metformin, bisphosphonates and GLP-1 receptor agonists. It’s an interesting prioritization and I almost agree with him. I like the table overview but the thing that I would like to improve in it is especially the ranking of preclinical lifespan studies around the ITP (= Intervention Testing Program) studies in mice. This is because the ITP is considered as the gold standard of lifespan studies in mice. So I have improved the ranking around this because as it is today then the lifespan data on Rapamycin outperforms currently all compounds that have been tested in the ITP throughout almost two decades. The ranking could be improved even more by including preclinical studies in multiple species and even there Rapamycin outperforms most compounds.

So by this small improvement in the ranking around preclinical lifespan studies then this will result in Rapamycin being among the compounds that the field should focus on. We just need the right clinical trials in humans which will hopefully come in the near future. My guess is that the data from those clinical trials will put Rapamycin to the top candidate in this ranking list. So it’s just a matter of time before this happens but it’s very frustrating that things go so slow forward.

One potential way of speeding up the research around Rapamycin is to start collaborating with a GLP-1 receptor agonists company and combine their intervention with Rapamycin to see if the potential longevity effects could be enhanced even more. I think this could be a very interesting thing because currently the GLP-1 receptor agonists have gotten a huge attention due to its weight loss effect and its multi-billion USD market. There are still some challenges that need to be sorted out and when that is done then one interesting combinational therapy to test is to combine it with Rapamycin. I think I will dig more into this and see if there exists some potential collaboration in this area. Any thoughts?

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Here is the ARDD 2024 clip with Nir Barzilai:

Here is the link to the ranking list paper:
https://doi.org/10.18103/mra.v12i2.5138

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New Paper: Summary of the top FDA-approved Drugs that can be Repurposed as Gerotherapeutics / Geroprotectors
Updated Prioritization of Geroscience-Guided FDA-Approved Drugs Repurposed to Target Aging - the most interesting findings in February 2024 Medical Research Archives?
Rapamycin expanded indications?
#2

He has always been a great fan of Metformin, but I think this is based upon the key papers being subject to selection bias.

An interestingly high placing of Methylene Blue.

I think he is wrong on mechanism, however.

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#3

I would never take this class of drugs. The bone docs don’t even like it except as a last resort. Too many problems.

His belief in metformin reminds me of the old quote about how science progresses: one funeral at a time.

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#4

Discussions about the previous versions of the list:

It’s a great framework and the overall results make sense. Still:

  • I’m surprised by bisphosphonates.
  • GLP1-RA don’t seem to extend lifespan in animal models and their benefits for people with diabetes, obesity or CKD are unclear.
  • ACEis and ARBs are different classes and shouldn’t be grouped together. There are intraclasses differences as well.
  • Beta-blockers have a MASSIVE intraclass heterogeneity. Their benefits are unclear in people without heart conditions. They could even be detrimental.

Might be missing: low-dose lithium?

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#5

Thank you for this. As you say, it is unlikely that any one drug is going to be the whole answer. I like what Ralph DeFronzo said in his recent interview with Peter Attia. To paraphrase briefly, speaking of diabetes, he is an advocate of using multiple drugs simultaneously to address the disease - as he says, diabetes is an incredibly complex disease, so why would you think that any one drug could ever fix all those issues at the same time; accordingingly, you inevitably must use many drugs simultaneously and that has been shown in his research (he’s the pioneer in discovering SGLTi, and also the one to bring metformin stateside from Europe).

I think it’s the same with aging. It must be addressed with multiple drugs and interventions. Polypharmacy is inevitable. But following that are the inevitable complications and conflicts. Some of these drugs are going to be additive in antiaging effects, and some negative in interactions. And because as individuals we all have our unique vulnerabilities, our optimized individual drug/intervention stacks are going to be different. The other thing to keep in mind is that some of these drugs will overlap in antiaging applicability just as they do in their primary indications. For example, although Ralph DeFronzo thinks metformin is a good drug, he thinks that for the treatment of diabetes it has been superseded by other drugs, so in his clinical practice he tends to prescribe the newer drug combinations, which don’t necessarily include metformin. The same situation might obtain for antiaging interventions. A drug such as perhaps metformin might have good effects against the aging process. But there might be other drugs or new drugs in the future which work on the same hallmarks, but along superior pathways, and once available continuing to use metformin might not make any sense. To use an analogy, if your objective is fast transport, using a horse (metformin) was a big advance, but when cars became available, it would have made no sense to keep using horses (except perhaps in special situations), so horses would disappear from our roads. Similarly metformin might be a good drug, but might be superseded by superior drugs in antiaging applications, and metformin would be dropped in this context. The exact same thing might happen to rapamycin as speculated by Matt Kaeberlein. According to him it is inevitable that there will be drugs that work on mTOR with superior outcomes for antiaging and will therefore completely replace rapamycin for antiaging. Rapamycin will continue to be a good drug, but no longer useful just as horses are no longer used for rapid transportation in most situations for the average human. This incidentally is the ambition of Joan Mannick with the research at Tornado.

As an example, in my own case of antiaging protocol I have rapamycin of course, and empagliflozin, but not metformin. However I also use a statin (pitavastatin), because my lipids are very poor. And even though statins have not made the table as an antiaging drug, I still need them in my unique situation to prevent atherosclerotic aging of my vasculature and possibly fatal MACE. So while statins are not antiaging per se, they are mortality ameliorating in my case.

Bottom line, polypharmacy is the way forward, with individualized drug stacks tailored to each one of our particular situations. This “precision” medicine approach makes it of course much more difficult, at this point in time, as we can’t just rely on population studies which are valid for the population, but obviously not fitted precisely to the individual.

So as I look at this table, it is great as a guide for future research directions, but of cautions application to the individual. Any single drug might rank high in the table, but low or not at all for me in particular.YMMV.

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#6

You might be interested in @John_Hemming’s “genomic failure hypothesis”:

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Analysis and suggestions of interventions by ChatGPT-4.5 Deep research: ChatGPT-4.5 Deep Research Genomic Failure Hypothesis Evaluation - Google Docs

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#7

Thanks, I’ll look into this. I’m very slow in adapting any new drugs/interventions… endless research😂. Right now, I’m very interested in your hypoxia journey (different thread), and following it closely, but sad to see so few updates. I was surprised to see the relatively small SpO2 drops employed.

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#8

Its actually the partial pressure in serum that ends up mattering rather than SP02.

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#9

I had to stop after 3 sessions because the clinic where I went was too far from home and the staff was stupid. I want to try it again but right now I’m trying other interventions so step by step…

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#10

For diabetes, not longevity. Although solving diabetes is good for living longer so there’s that. I was surprised to learn that metformin is a fairly new drug (30 years?) in the USA.

#11

@John_Hemming: Yes, he is biased on metformin that is good to keep in mind and much also because of the TAME trial which he has tried to get started for many years.

Regarding the mechanism, what specifically do you think he is wrong about? That metformin targets all hallmarks? It was in this paper he talked about it Benefits of Metformin in Attenuating the Hallmarks of Aging - PubMed

@约瑟夫_拉维尔 Thanks for sharing your view on the topic. I have no knowledge about bisphosphonates but different people have reacted in the same way as you. One thing I think can be good to keep in mind is that this list is not a verified longevity compound list. It is just a list with compounds that Barzilai thinks has longevity potential. I think that is important to point out so that people don’t start to think these are the compounds to start using.

@adssx Big thanks for sharing this! Regarding low dose lithium, what points would you give to that in the different column areas?

@CronosTempi Big thanks for a great post! Here is the podcast with Ralph DeFronzo you mentioned. I have not yet listened to it but will add it to my list.

I really like the metaphor also with horses and cars and that compounds will naturally be replaced by better ones. I agree with Kaeberlein here also that a better mTOR inhibitor will be discovered that I think will outperform rapamycin. I think for example that the dual PI3K/mTOR inhibitor Omipalisib, also known as GSK2126458 and GSK458, has interesting potential. Last week I sent in a ITP proposal on that compound together with other researchers. I think the case to test it is quite strong but the tricky thing will be to use the right dose. Too high will be toxic and too low will not have any significant effect. But I have a good feeling that we will have a dose with some type of effect.

Regarding statins, I don’t know if you have listened to this podcast episode with Kaeberlein where he goes through some interesting compounds with potential. Low dose of Rosuvastatin is an interesting one.

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#12

Bisphosphenates have the same grades as metformin? How and why?

Bisphosphenates (eg fosamax) destroy the osteoclasts in the bone so that non-functional senescent cells remain there. The DXA scan shows higher bone mineral content but the bones have the crystalline structure of saltines. That’s why you are seeing the strange cross-femur non traumatic fractures. So the bisphosphenates make your DXA numbers better but in fact the bones are weaker.

Also, since osteoclast activity is required to signal osteoblasts to make new bone cells, the bisphosphenates are a double whammy – more non working senescent cells left behind and fewer new cells.

This is scary – if it can be so wrong about bisphosphenates, how trustworthy is any of the information on any of the drugs? Please someone argue with me.

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#13

Zoledronic acid reduce hip fracture rates in its randomized trial, so why would you believe the bones are weaker?

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#14

There was at least one paper I looked at on Metformin that basically excluded people who got too ill for Metformin. In fact that paper found the healthiest people were those that had diabetes, but died before they needed any other medication.

If you compare that to people who don’t have diabetes then you cannot rely on the analysis.

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#15

I’ve been using Rapamycin for over 2…5 years, every other week 6mg.

I’ve been using Tirzepatide (Aug 2023) and now Retatrutide (Apr 2024) since August of 2023. Just over 18 months now.

Prior to using the GLP1-R’s my annual blood tests were OK’ish with anywhere from 3 to 6 (2023) markers in the red out of 26 markers. Today only 2 in the red;

  1. WBC EOSINOPHILS
  2. B-12 was/is too high - first test was way too high, most recent is very close to high normal.

I cut back on the B-12 supplement and it improved in 3 months, another test in 6 months will tell the tale.

My DNAm testing with Trudiagnostic showed improvements from 2021 to 2024 with the best improvements coming after the addition of the GLP1-R’s. My DunedinPace is the best it’s been in 5 tests over 4 years.

Being at a better weight is obviously beneficial and the improved glucose control with GLP1-R’s is also an obvious benefit for me.

How one would run a combinatorial study on humans with these 2 interventions would be interesting to see.

I’m not a big fan of mouse studies as a true indicator of how something will perform in humans. I do get why these are done but until I see human studies, I remain hopeful but cautiously skeptical with my enthusiasm.

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#16

OK, I’ll argue :slight_smile:

I have never looked into this family of drugs before so you are way more knowledgeable than I am.

Doesn’t look like they “destroy” rather they inhibit…

The risk is well understood and there is a process to mitigate that risk.

The optimal duration of oral bisphosphonate therapy is typically 5 to 10 years, and for intravenous (IV) bisphosphonates it’s 3 to 6 years. This varies based on your individual fracture risk at one time. Beyond this, a “drug holiday” or withdrawal period is recommended to prevent harmful accumulation of the medicine. After this break, bisphosphonates are often resumed without long-term complications, after proper time lapsed for the natural remodeling process to reset and function normally.

Looks like excessively high dosing may be the culprit.

There is the argument you asked for :slight_smile: but I don’t disagree with you, it looks to me like a risky family of compounds to avoid and I’d be looking for another solution.

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#17

Aspirin is in the list. It is so tempting. It’s been around so long that it feels like a vitamin. I’ll find a way to use it again.

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#18

A bit more about bisphosphenates: as the articles said, it works by slowing down the removal. But slowing down the removal of senescent cells is not helpful because senescent cells do not add strength to the bones. And the only meds that stimulate new bone cell development are the parathyroid anabolics such as Forteo and Tymlos. But the gains are quickly lost once you stop taking these (you can take for only 18-24 months). So then, women are told to get on Prolia, a monoclonal antibody that works similarly to the bisphosphenates, or a bisphosphenate such as fosamax, or the injectable form, reclast or zoledronic acid. If you stop taking these follow-up drugs you go back to the level you were at before starting the anabolics, often in about 18 months.

What most women are not advised to do is get bone marker tests – a blood test that measures 4 things --one of them shows whether in fact levels of resorption are higher than they should be.It is true that they do tend to rise after menopause, but not in all women. I did not get the bone markers done until many years after having stopped the fosamax (and started estradiol/prometrium). My resorption levels were not too high. If your resorption levels are high, then it might be helpful to take a bisphosphenate for a short time. But without the bone marker test you will not know if they will be helpful or harmful for you.

I wish I had not ever taken a bisphosphenate. I do hope that enough time has passed that we will not discover that other interventions such as metformin (I am on 1000mg / day) has surprise unwanted consequences for some people.

Incidentally, the article says that there are several good drugs for osteoporosis. No, there are not, there are none really. We do not know how to make new bone cells grow in any sustainable way.

I hate to say it but it has the ring of what is happening with Alzheimers – looking for a silver bullet drug that will fix what is basically the outcome of a complex metabolic process. The new drug lecanemab will slow down formation of tau and beta amyloid in some people. But we are now starting to understand that phosphorylated tau and amyloid beta are the response to a problem and not the underlying problem themselves. The underlying problem is metabolic, with some genetic propensities, and now perceived to be inflammatory “type 3 diabetes.”

The best things we know for bones is similar to what we know for general well being: avoid inflammation, avoid the kinds of foods that stimulate inflammation, do frequent exercise with some weight bearing, and get sufficient K2 MK7 and MK4, D, magnesium, calcium (but not calcium without the other four).

The only drug I know of that might help the bone remodelng process even a little is raloxifene, a selective estrogen reuptake modulator. It is long studied, generic (for Evista), relatively quite safe (some risk of blood clots). In the bones it acts like a (weak) estrogen but in the breast it blocks the uptake of estrogen (similar to tamoxifen but not as potent, and without the tamoxifen sides). The risk reward profile for post menopausal women is pretty compelling yet we never hear about raloxifene.

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#19

Below is a detailed summary of the key studies that led to the approval of bisphosphonates for osteoporosis treatment, including specific outcomes such as risk reduction, hazard ratios (HR), and relative risk (RR) where available.

1. FIT (Fracture Intervention Trial)

Drug: Alendronate (Fosamax)
Population: Postmenopausal women with osteoporosis (low bone mineral density and/or prior vertebral fractures).

Key Outcomes:

  • Vertebral Fractures:
    • Risk Reduction: 47% reduction in vertebral fractures (RR = 0.53, 95% CI: 0.41–0.68).
    • Absolute risk reduction: 6.2% vs. 11.3% in placebo.
  • Hip Fractures:
    • Risk Reduction: 51% reduction in hip fractures (RR = 0.49, 95% CI: 0.23–0.99).
    • Absolute risk reduction: 0.7% vs. 1.4% in placebo.
  • Non-Vertebral Fractures:
    • Risk Reduction: 26% reduction (RR = 0.74, 95% CI: 0.59–0.92).
  • Bone Mineral Density (BMD):
    • Significant increases in BMD at the spine (8.8%) and hip (5.9%) over 3 years.

2. VERT (Vertebral Efficacy with Risedronate Therapy)

Drug: Risedronate (Actonel)
Population: Postmenopausal women with osteoporosis (vertebral fractures or low BMD).

Key Outcomes:

  • VERT-MN (Multinational Trial):
    • Vertebral Fractures:
      • Risk Reduction: 41% reduction (RR = 0.59, 95% CI: 0.43–0.82).
      • Absolute risk reduction: 11.3% vs. 16.3% in placebo.
    • Non-Vertebral Fractures:
      • Risk Reduction: 39% reduction (RR = 0.61, 95% CI: 0.39–0.94).
  • VERT-NA (North American Trial):
    • Vertebral Fractures:
      • Risk Reduction: 49% reduction (RR = 0.51, 95% CI: 0.36–0.73).
    • Non-Vertebral Fractures:
      • Risk Reduction: 33% reduction (RR = 0.67, 95% CI: 0.44–1.04).
  • BMD:
    • Significant increases in spine (5.4%) and hip (3.1%) BMD over 3 years.

3. HORIZON (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly)

Drug: Zoledronic Acid (Reclast)
Population: Postmenopausal women with osteoporosis.

Key Outcomes:

  • Vertebral Fractures:
    • Risk Reduction: 70% reduction (RR = 0.30, 95% CI: 0.24–0.38).
    • Absolute risk reduction: 3.3% vs. 10.9% in placebo.
  • Hip Fractures:
    • Risk Reduction: 41% reduction (RR = 0.59, 95% CI: 0.42–0.83).
    • Absolute risk reduction: 1.4% vs. 2.5% in placebo.
  • Non-Vertebral Fractures:
    • Risk Reduction: 25% reduction (RR = 0.75, 95% CI: 0.64–0.87).
  • BMD:
    • Significant increases in spine (6.7%) and hip (5.1%) BMD over 3 years.

4. BONE (Oral Ibandronate Osteoporosis Vertebral Fracture Trial)

Drug: Ibandronate (Boniva)
Population: Postmenopausal women with osteoporosis.

Key Outcomes:

  • Vertebral Fractures:
    • Risk Reduction: 52% reduction (RR = 0.48, 95% CI: 0.34–0.69).
    • Absolute risk reduction: 4.7% vs. 9.6% in placebo.
  • Non-Vertebral Fractures:
    • No significant reduction in non-vertebral fractures (RR = 0.85, 95% CI: 0.66–1.09).
  • BMD:
    • Significant increases in spine (6.5%) and hip (3.4%) BMD over 3 years.

5. Other Studies

Men and Glucocorticoid-Induced Osteoporosis:

  • Alendronate in Men:
    • Vertebral Fractures: 89% reduction (RR = 0.11, 95% CI: 0.02–0.50).
    • BMD: Significant increases in spine (7.1%) and hip (2.5%) BMD over 2 years.
  • Risedronate in Glucocorticoid-Induced Osteoporosis:
    • Vertebral Fractures: 70% reduction (RR = 0.30, 95% CI: 0.14–0.64).
    • BMD: Significant increases in spine (4.3%) and hip (2.8%) BMD over 1 year.

Summary of Key Findings:

  • Vertebral Fractures: Bisphosphonates consistently reduced vertebral fracture risk by 41–70%.
  • Hip Fractures: Significant reductions (up to 51%) were seen with alendronate and zoledronic acid.
  • Non-Vertebral Fractures: Reductions ranged from 25–39%, with some variability between drugs.
  • BMD: All bisphosphonates significantly increased BMD at the spine and hip, with improvements ranging from 3–9% over 2–3 years.

These outcomes formed the basis for regulatory approval of bisphosphonates as first-line treatments for osteoporosis. The consistent reduction in fracture risk and improvement in BMD across multiple populations (postmenopausal women, men, and glucocorticoid-induced osteoporosis) demonstrated their efficacy and safety.

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Yes, evidence has emerged suggesting that long-term use of bisphosphonates may be associated with an increased risk of certain atypical fractures, particularly atypical femoral fractures (AFFs). These fractures are rare but have been linked to prolonged bisphosphonate use. Below is a detailed overview of the evidence and mechanisms:

Atypical Femoral Fractures (AFFs)

AFFs are rare, low-energy fractures that occur in the subtrochanteric region or femoral shaft (the long part of the thigh bone). They are distinct from typical osteoporotic hip fractures, which occur in the femoral neck or intertrochanteric region.

Key Evidence:

  1. FDA Safety Review (2010):
  • The FDA conducted a review of bisphosphonate safety and identified a potential link between long-term use (typically >3–5 years) and AFFs.
  • The risk was estimated to be 1–10 cases per 10,000 patient-years, which is low but statistically significant.
  1. ASBMR Task Force Report (2010):
  • The American Society for Bone and Mineral Research (ASBMR) published a task force report defining AFFs and highlighting their association with bisphosphonate use.
  • The report noted that while the absolute risk is low, the relative risk increases with longer duration of use.
  1. Large Observational Studies:
  • Study by Schilcher et al. (2011):
    • This Swedish study found that the risk of AFFs increased with longer duration of bisphosphonate use.
    • After 4–5 years of use, the risk was 10 times higher compared to non-users.
    • However, the absolute risk remained low (approximately 50 cases per 100,000 patient-years).
  • Study by Dell et al. (2012):
    • This study analyzed data from over 1.8 million women and found that the risk of AFFs increased with longer duration of bisphosphonate use.
    • The risk was highest after 7–8 years of use, but the absolute risk was still low (approximately 100 cases per 100,000 patient-years).
  1. Meta-Analyses:
  • A 2016 meta-analysis confirmed that bisphosphonate use is associated with a 2–3 times higher risk of AFFs, but the absolute risk remains very low (less than 1% over 10 years of use).

Mechanism of AFFs

The exact mechanism is not fully understood, but it is thought to involve oversuppression of bone turnover:

  • Bisphosphonates inhibit osteoclast activity, which reduces bone resorption but can also lead to accumulation of microdamage over time.
  • This microdamage can weaken the bone structure, particularly in weight-bearing areas like the femur, making it more susceptible to atypical fractures.

Other Fracture Risks

While AFFs are the most well-documented concern, there is limited evidence suggesting a potential increased risk of other fractures:

  1. Osteonecrosis of the Jaw (ONJ):
  • Although not a fracture, ONJ is a rare but serious complication associated with bisphosphonate use, particularly in cancer patients receiving high-dose intravenous bisphosphonates.
  • The risk in osteoporosis patients is very low (approximately 1 in 10,000 to 1 in 100,000).
  1. Stress Fractures:
  • Some studies suggest that prolonged bisphosphonate use may increase the risk of stress fractures in other bones, but the evidence is less clear.

Balancing Risks and Benefits

While the risk of AFFs is a concern, it is important to weigh this against the significant benefits of bisphosphonates in reducing osteoporotic fractures:

  • Bisphosphonates reduce the risk of vertebral fractures by 40–70% and hip fractures by 40–50%.
  • The absolute risk of AFFs remains very low compared to the risk of osteoporotic fractures, which are associated with significant morbidity and mortality.

Clinical Recommendations

To mitigate the risk of AFFs, guidelines recommend:

  1. Drug Holidays:
  • After 3–5 years of treatment, consider a “drug holiday” for patients at lower risk of fracture (e.g., those without prior fractures and stable BMD).
  • High-risk patients may continue treatment but should be monitored closely.
  1. Monitoring Symptoms:
  • Patients on long-term bisphosphonates should be advised to report any thigh or groin pain, which could be a warning sign of an impending AFF.
  1. Regular Reassessment:
  • Reassess fracture risk and treatment duration periodically (e.g., every 3–5 years).

Conclusion

While bisphosphonates are highly effective in reducing osteoporotic fractures, long-term use has been associated with a small but increased risk of atypical femoral fractures. The absolute risk remains low, and the benefits of fracture prevention generally outweigh the risks. However, clinicians should monitor patients on long-term therapy and consider drug holidays in appropriate cases.

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#20

Thanks, Krister. Yes, I saw that podcast at the time it came out, atorvastatin 10-20mg lowered HR very slightly(0.91), 40-80mg raised it. Statins as a class in the UK biobank database were ever so slightly OK (HR 0.97), but that was all statins at all doses. Simvastatin failed the ITP (neutral), but mice don’t tend to get CVD. From my reading of the literature, there seems to be some ACM and CVD mortality benefit in humans, but for life extension the signal is very weak and possibly nonexistant (in animal models). So I’m sticking to my original assessment of statins - lowering mortality, especially for those who need it for CVD risk amelioration, but not life extending per se (as in: slowing aging). I do believe statins extend healthspan in those that tolerate them, but it’s possible that other drugs can accomplish the same targets perhaps better - lowering lipids, protecting the vasculature, loweing systemic inflammation etc.

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