Thoughts on David Sinclair research

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Runnerman

New Member
Recently stumbled on a lot of interviews with longevity scientist and researcher David Sinclair. Many on YouTube. He is saying that research is showing that eating less and having longer periods of fasting activate genes that keep us younger and healthier. He is eating a mostly plant based diet. He has been basically eating one decent size meal a day for the past several years and says he feels better and looks younger. Some of the keys being a long period of fasting. Keeping glucose levels as low as possible. Just wondering what some of you thought about his ideas and research if you are familiar with it.
 
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Guided_by_Voices

Well-Known Member
Anti-aging is a huge topic. I would recommend Josh Mittledorf's Aging Matters Blog and Paul Jaminet's Perfect Health Diet as a starter set of reading. One of the primary mechanisms behind Time Restricted Eating seems to be keeping insulin down, since chronically elevated insulin seems to drive almost every major disease state (Cancer, Dementia, CVD, and others.) Paul Jaminet has an excellent view on what healthy plant-based really means, and it doesn't mean there is anything inherently wrong with animal products.
 

Belekas

Active Member
Been hearing his name a lot over the years but never followed him so it's interesting to me as well. Following.
 

SteveCleves

New Member
I think its pretty well accepted as conventional wisdom in the longevity world that calorie restriction, whether through actual calorie restriction or through tricking the body into thinking your calorie restricted, is a key to longevity.

At the risk of "knowing just enough to sound stupid"...I think the theory is basically when the body thinks its starving it slows down all the growth and aging systems.
 

FunkOdyssey

Well-Known Member
I was a moderator of a longevity forum for many years, called the Immortality Institute in the early days and now Longecity.org. That gave me a front row seat to the rise and fall of resveratrol and Sinclair's fall from grace along with it. Somehow, he has managed to rebrand himself as the public face of anti-aging science after writing a very popular book, Lifespan: Why We Age and Why We Don't Have To.

The most exciting compounds available right now are rapamycin and senolytics, including fisetin, dasatinib, and quercetin. These may actually slow or reverse signs of aging. Rapamycin consistently extends lifespan in animal studies even when started in mid or late life. I've been trying to get my father to start on it with Dr. Alan Green who prescribes it via telemedicine.

Peter Attia doesn't have a book but he is a better source of information in my opinion if the topic interests you.


Back to Sinclair, listen to him talk for five minutes about TRT and why he thinks it will shorten our lifespans in this podcast:

The basis for his opinion is purely theoretical: factors that suppress growth and reproduction generally extend life (IGF-1 knockout, mTOR inhibition, calorie restriction). Testosterone supports tissue growth and reproduction so it must shorten lifespan.

Two of the very best predictors of how much time you have left are your grip strength and walking speed. What effect do you think testosterone will have on those parameters?

The only facts cited to support his position are that eunuchs have been observed to live longer than intact males. There is no acknowledgement of other variables that could have influenced their longevity. In my opinion his thinking is sloppy.
 

Belekas

Active Member
I was a moderator of a longevity forum for many years, called the Immortality Institute in the early days and now Longecity.org. That gave me a front row seat to the rise and fall of resveratrol and Sinclair's fall from grace along with it. Somehow, he has managed to rebrand himself as the public face of anti-aging science after writing a very popular book, Lifespan: Why We Age and Why We Don't Have To.

The most exciting compounds available right now are rapamycin and senolytics, including fisetin, dasatinib, and quercetin. These may actually slow or reverse signs of aging. Rapamycin consistently extends lifespan in animal studies even when started in mid or late life. I've been trying to get my father to start on it with Dr. Alan Green who prescribes it via telemedicine.

Peter Attia doesn't have a book but he is a better source of information in my opinion if the topic interests you.


Back to Sinclair, listen to him talk for five minutes about TRT and why he thinks it will shorten our lifespans in this podcast:

The basis for his opinion is purely theoretical: factors that suppress growth and reproduction generally extend life (IGF-1 knockout, mTOR inhibition, calorie restriction). Testosterone supports tissue growth and reproduction so it must shorten lifespan.

Two of the very best predictors of how much time you have left are your grip strength and walking speed. What effect do you think testosterone will have on those parameters?

The only facts cited to support his position are that eunuchs have been observed to live longer than intact males. There is no acknowledgement of other variables that could have influenced their longevity. In my opinion his thinking is sloppy.
Grip strength and walking speed?
 

Runnerman

New Member
Thank you everyone for the responses. I may not have looked into this enough but on the surface he doesn’t seem to be pushing any specific plans or supplements etc. His podcasts are supported by some sponsors which they acknowledge and thank during the podcasts. Athletic Greens being one. I guess if he is selling off his research or technology to big companies that could raise some eyebrows.

The one question for me about the fasting is whether the body adapts over time to that one meal a day and comes to accept that as the new norm. So it doesn’t perceive that as a physically stressful state but accepts it as everything is ok. Maybe that’s not how it works. He does say somewhere that their research is showing that simply restricting calories while eating 3 meals a day doesn’t have that same affect. It has to be combined with a large period of fasting at least according to their research.

It will be interesting to see what else comes out of this.
 
Contoversial. Sinclair's work on resveratrol has apparently been debunked. His results could not be replicated. In the meantime he made 720 million selling the technology to Glaxo.

Is Sinclair or Stanfield bunk?

I would not go so far as to say 'debunked', but Dr Stanfield has raised serious questions that Dr Sinclair has so far dodged. It might be because he's embarrassed by Dr Stanfield's questions, or he might simply look at Dr Stanfield as an attention-hunting newbie. Either way, I really feel Dr Stanfield's questions have merit and I do wish Dr Sinclair would respond in a credible manner. Dr Stanfield invited him to sit down face-to-face to discuss the concerns, but that went nowhere. I'm not writing off either one - Dr Sinclair, even if resveratrol does turn out to a big nothing, has made amazing discoveries and advancements in our understanding of aging, and Dr Stanfield does an outstanding job of breaking down complex studies into layman's turns so people like me can understand them. Following both closely.
 
One more thing. Based on current evidence, being big and strong appears to conflict with living a long time, mostly due to the calories and food required to attain and maintain that strength and size, which conflicts with the fasting requirements Dr Sinclair (and many others) promote. Think about it - does Dr Sinclair look like he lifts?
 

Runnerman

New Member
Happened to find this article which mentions a dizzying number of connections to companies and labs and universities.

KHN article

Hard to tell what this all means.

@lunchbeast - You’re right, he‘s probably not trying to bulk up. One podcast he mentioned weighing around 150+ lbs when he started the fasting a few years ago. Now I think he mentioned being in the 130+ lbs
 
I think you’re either one type of person or the other. Do you want to focus on being muscular and eating surplus calories and be on trt or do you want to take rapamycin and live longer with potentially longer healthspan/lifespan. For those who have kids maybe the latter would be the better choice. I don’t think being on trt and taking rapamycin makes sense.
 

Vtail

Active Member
I think you’re either one type of person or the other. Do you want to focus on being muscular and eating surplus calories and be on trt or do you want to take rapamycin and live longer with potentially longer healthspan/lifespan. For those who have kids maybe the latter would be the better choice. I don’t think being on trt and taking rapamycin makes sense.
Does it have to be one or the other? Why can't you do TRT and Rapamycin, and get the best of both worlds?
 

FunkOdyssey

Well-Known Member
Grip strength and walking speed?
Grip strength, gait speed, chair stand test -- these basic physical function tests are the biomarkers that rule them all. They predict everything from depression, cognition, surgery recovery, CHD risk, cancer risk, dementia risk, and most importantly all-cause mortality. Here's a good free text review: Grip Strength: An Indispensable Biomarker For Older Adults - PubMed

Here's a typical study associating grip strength with all-cause mortality:

handgrip strength graph.jpg


The literature on this is overwhelming to the point that I don't even know where to start to present some interesting findings. I searched "gait speed mortality" on pubmed and it returned over 900 results: gait speed mortality - Search Results - PubMed

So this is where I think the research anti-aging scientists are doing in lower life forms may not directly translate to human longevity. If you restrict calories and protein and avoid anything anabolic you might reduce your cellular rate of aging and then become so frail, sarcopenic and osteoporotic that you die anyway from a simple fall.

I think you’re either one type of person or the other. Do you want to focus on being muscular and eating surplus calories and be on trt or do you want to take rapamycin and live longer with potentially longer healthspan/lifespan. For those who have kids maybe the latter would be the better choice. I don’t think being on trt and taking rapamycin makes sense.

I would like to pursue the hybrid approach and I don't see why you wouldn't. Look at Peter Attia, he talks often about how he is training for the "centenarian olympics" and is very concerned with carrying enough muscle mass into old age to maintain his mobility and physical function, while using time-restricted feeding, periodic fasting, and a weekly dose of rapamycin to slow his aging. I suppose professional bodybuilding is incompatible with longevity but there's no reason you can't be both athletic and long-lived.

Testosterone probably has a mixture of dose-dependent positive and negative effects on longevity, and the net effect doesn't seem obvious to me. Contrast with growth hormone: GH and IGF-1 are without question having a strong negative impact on lifespan at increasing levels. That's definitely one to avoid if you are concerned.
 
Correct me if I’m wrong, but I don’t think Peter attia is on trt. None of those longevity doctors and scientists are. Even Huberman mentioned stopping trt after one year. Also i mean trt does increase gh and igf-1 and also shortens telomeres. I would also like to add that rapamycin only increased mouse lifespan by 15 percent so I’m assuming it’s lower in humans. So not sure if risks outweigh benefits of taking it. Peter doses it at 8-10 mg weekly and complains constantly of getting mouth ulcers.
 

FunkOdyssey

Well-Known Member
Correct me if I’m wrong, but I don’t think Peter attia is on trt. None of those longevity doctors and scientists are. Even Huberman mentioned stopping trt after one year.
I don't think they are on TRT but why would they be if they weren't hypogonadal? Did Huberman explain why he stopped? As far as I know, the only reason he started was to develop some firsthand experience for a book he is writing on hormone optimization.

Also i mean trt does increase gh and igf-1 and also shortens telomeres.

To the extent that TRT increases GH and IGF-1, that would be a negative effect among a mix of positive and negative effects of TRT on longevity. And what makes you think TRT shortens telomeres in human men? Some researchers are suggesting testosterone supplementation for the express purpose of lengthening telomeres:

In men, serum DHT and E2 correlate with LTL independently of age. Aromatase gene polymorphisms include three dominant alleles that are associated with both lower serum E2 and shorter LTL. Haplotype analysis demonstrated one common haplotype that was associated with lower serum E2 and shorter LTL. Although replication in other cohorts and further investigation of the effects of DHT are required, these results suggest a putative role for circulating E2 in the regulation of telomere length in vivo. Further studies are warranted to examine whether interventions involving T supplementation via its metabolism to DHT and E2 might slow biological aging and thereby preserve health in men.

I would also like to add that rapamycin only increased mouse lifespan by 15 percent so I’m assuming it’s lower in humans. So not sure if risks outweigh benefits of taking it. Peter doses it at 8-10 mg weekly and complains constantly of getting mouth ulcers.

The effects on mouse lifespan are variable but always positive and in some cases very impressive:

rapamycin mouse lifespan.png


Peter pushes the envelope of rapamycin dosing and that's why he has the mouth ulcers. I experimented with it at 5 mg weekly and had no trouble with that, although it did make my thumb twitch. It's like TRT or anything else where you can titrate dose to prevent side effects.
 
I don't think they are on TRT but why would they be if they weren't hypogonadal? Did Huberman explain why he stopped? As far as I know, the only reason he started was to develop some firsthand experience for a book he is writing on hormone optimization.



To the extent that TRT increases GH and IGF-1, that would be a negative effect among a mix of positive and negative effects of TRT on longevity. And what makes you think TRT shortens telomeres in human men? Some researchers are suggesting testosterone supplementation for the express purpose of lengthening telomeres:





The effects on mouse lifespan are variable but always positive and in some cases very impressive:

View attachment 24563

Peter pushes the envelope of rapamycin dosing and that's why he has the mouth ulcers. I experimented with it at 5 mg weekly and had no trouble with that, although it did make my thumb twitch. It's like TRT or anything else where you can titrate dose to prevent side
Yea I mean huberman gave that response and I was like what? Not sure i believe that’s the reason. But he’s buddy buddy with all those longevity experts and doctors so who knows? And what’s your definition of hypogonadal because every doctor has their own definition of what that is apparently. T does shorten telomeres I have to find the pubmed article.
 

FunkOdyssey

Well-Known Member
I saw that study but it isn't clear that the free-living songbird is a good proxy for us on TRT, if higher DHT and E2 in men correlates with longer telomeres. Every human study I find on this topic is showing that either T or its metabolites DHT and E2 are associated with longer telomere length.

In conclusion, compared with matched controls, LTL, plasma level of T and DHT were significantly decreased in male IPF patients. Plasma T was associated with LTL independent of age and rare protein‐altering variants in telomerase‐related genes. No genetic variations in the exons of androgen‐related pathway genes were associated with the T level. Our study suggests that lower level of T might play a role in the shorter LTL in male IPF patients apart from rare variants in telomerase‐related genes. Future research is needed to examine whether hormonal interventions might retard telomere loss in male IPF patients and whether such retardation is associated with clinically important outcomes.

In older men, neither T nor DHT is associated with LTL while E2 is independently associated with LTL and SHBG is inversely associated, thus relating sex hormone exposure to lower biological age. Further research is needed to determine causality and clarify the role of sex hormones in male ageing.

Don't tell Danny higher E2 lengthens telomeres or we'll never hear the end of it.
 

FunkOdyssey

Well-Known Member
The results of a very large prospective study (150k men) on the relationship between testosterone level and mortality that also cites many previous studies in the discussion:

Previous studies have reported no associations of testosterone concentrations with mortality,6-10 or associated lower testosterone with higher all-cause mortality.11-17 Similarly, associations of testosterone concentrations with cardiovascular disease (CVD)-related deaths are inconsistent: some studies reported no associations,6,8,10,13,17,18 others inverse associations.11,12,14,15,19 Cancer is another major cause of deaths. Testosterone concentrations have been inversely associated with cancer mortality in some studies,11,16 positively associated in one,22 and not associated in others.12,19 Several cohort studies have reported no association of SHBG concentrations with mortality, nor with deaths from CVD.6,8,17-20 Other studies in middle-aged and older men,21,22 and men with diabetes,23-25 associated higher SHBG concentrations with mortality. In addition to inconsistent results, the heterogeneity of these studies with respect to geography, participant selection and covariates included in different analytical models, adds further uncertainty to the findings.

To accommodate the relationship between serum testosterone and SHBG, free testosterone is commonly calculated from (total) testosterone and SHBG using formulae based on mass action equations (calculated free testosterone, cFT).26,27 Some studies reported similar findings for cFT and (total) testosterone concentrations with respect to mortality in men,10,16,19 whereas some reported associations of low cFT but not (total) testosterone with all-cause7,9 or CVD-related mortality.22 Thus, studies of cFT and mortality risk in men have reported inconsistent results, and it remains unclear whether cFT offers additional information over testosterone alone for mortality-related outcomes.

This large cohort study of middle-aged and older men demonstrates that serum testosterone and cFT are inversely associated with overall and cancer-related, but not CVD-related mortality. The study also demonstrates direct relationships between serum SHBG and overall, CVD-related and cancer-related mortality.

Previous studies of testosterone and mortality have been smaller, generally analysing between one to five thousand men, with several hundred to a thousand or more deaths.6-18 A nested case-control analyses drawn from a cohort of 11,606 men involved 825 men who died (369 CVD-related, 304 cancer-related) and 1,489 controls.11 The largest previous cohort analysis involved 5,350 men, with 1,533 deaths (428 CVD-related, 480 from cancer-related).19 Our analysis of 149,436 men from the UK Biobank, with 10,053 deaths (1,925 CVD-related, 4,927 cancer-related) provided unprecedented scope to clarify the associations of testosterone and SHBG with all-cause, CVD and cancer mortality, and to establish more precise estimates of effect sizes.

Additionally, previous multivariable models typically adjusted for between five to ten covariates,7,9,10,12-15,19,22 while more extensive models included 11 to 18 covariates.6,11,18,23 We adjusted for 26 covariates including age, and not only BMI but also waist circumference. Importantly, and unlike previous studies, we included adjustment for specific factors that raise SHBG, such as thyroid and liver disease and anticonvulsant medications.5

In unadjusted analyses, men with lower serum testosterone had higher risks of death from any cause, CVD and cancer. However, in multivariable analyses including SHBG, only men with the lowest testosterone concentrations had higher all-cause and cancer-related, but not CVD-related, mortality. Previous studies including SHBG in the model found either inverse associations,11,18 or no association9 of testosterone with all-cause mortality. Other studies adjusting for risk factors and comorbidities, not including SHBG, reported inverse12,13,15,16 or neutral6,7,19,22 associations of testosterone with all-cause mortality. In our fully-adjusted analysis, the inverse association of testosterone with all-cause mortality was independent of SHBG. The association was statistically robust, but largely limited to men with testosterone in the lowest quintile, who had a modest (14%) increase in risk

Several previous studies reported no associations of testosterone with CVD-related mortality,6,8,10,13,17,18 whereas others reported inverse associations of testosterone with CVD deaths.11,12,14,15,19 After adjusting for covariates including SHBG, we found no evidence that testosterone was associated with risk of CVD death. The HR was 1.01, with narrow confidence intervals (0.86-1.18), arguing against any substantive association of testosterone with this outcome.

Two previous studies suggested a relationship between lower testosterone concentrations and cancer-related mortality,11,16 whereas another study associated higher testosterone with deaths from lung cancer,22 and other studies have reported no association of testosterone with cancer deaths.12,19 We found a robust inverse association, which was limited to men with serum testosterone in the lowest quintile, who had a modest (20%) increase in risk of dying from cancer.

Associations of cFT with all-cause, CVD and cancer-related mortality were seen in univariable analyses. However, in multivariable analyses these were attenuated: men with the lowest cFT values had higher all-cause and cancer-related, but not CVD-related mortality. Results for cFT, adjusted for covariates, did not provide additional information beyond analysis of testosterone and SHBG for mortality outcomes.

The relationships between testosterone and various types of mortality are always either inverse or neutral. There's no sign here that testosterone is a longevity-reducing hormone (in the physiological range).
 
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