989 replies to this topic

[Castiel]

It turns out there are only 4 overlapping values between PhenoAge and Age.AI 3.0: albumin, creatinine, Glucose and MCV. The other 5 values from PhenoAge (excl. chronological Age), namely C-reactive protein, Lymphocyte %, RDW, ALP and WBC are not included in Age.AI 3.0.

 

I adjusted my actual 2019 blood values for the 4 overlapping blood tests to the 'optimum' values, which in the case of PhenoAge reduced my 'real' result from 30 to 9yo. The result on Age.AI 3.0 was less dramatic, down from the 'real' result of 23 to 20. The PhenoAge delta of real to optimal was 21 years improvement, but the Age.AI 3.0 delta was only 3 years of improvement, albeit from a much lower base.

 

Atleast we know that both PhenoAge and Aging.AI 3.0 moved in the same direction (reduced biological age) with the 'optimal' blood marker values.

 

At this point I'd probably put more weight on the PhenoAge method, due to its more realistic result being closer to my chronological age (42yo) and cell based aging test results (telomeres 38.2yo, 2019; methylation 37.7yo, 2021), although its dependence on less variables might make it vulnerable to more wild swings.

 

I'd still place more weight on measurement of cell based aging using methylation markers or telomeres than a blood test estimate. 

 

And I'd put real biomarker results (BP, HRV, Pulse, Reaction Time, etc) above the results from a cell age based estimate.

 

That is just my opinion at the moment, but all feedback is good in our quest for more (healthy) life.

 

Hey the phenoage blue cells input calculator online does that give you phenoage for free if you put in the values, or is phenoage a paid service?    As for aging ai, yeah I suspected it wouldn't budge lower than 20 given that was the lowest age it was trained on, iirc, according to youtuber Michael Lustgarten.

 

Also kept going on the research on melatonin.   And was reading some of the stuff from the independent self taught researcher Jeff T Bowles.   Some of his writings on programmed aging seem to make a lot of common sense, and he goes into more detail in his article.

 

Very interesting article by independent researcher Jeff T Bowles

 

"Well, recently Craig Atwood did a study of changes in the pro-aging hormones  LH and FSH various species including the semelparous Salmon. Altough apparently he could not find any data on changes in LH levels in Salmon he did find that FSH levels skyrocket 4,500% post reproduction as compared to even the high level reached in humans after age 50 of about a 500% increase.

I would like to point out to Craig that there is a 1998 study on hormone changes in Salmon that shows LH levels skyrocket as well.  Biol Reproduction 1998 Mar;58(3):814-20. B. Borg et. al.

So the bottom line here is we see that semelparous species no longer have to be put in a special category and hidden away and ignored as not related to normal aging. Rather they now provide a somewhat typical case of programmed aging being driven by the post reproductive dramatic increases in FSH and LH  seen also in humans and most other animals from fish to mammals to birds, etc. The salmon are only unusual in the speed at which they age and the height to which their LH and FSH levels can reach."

 

 

https://jefftbowles....-is-programmed/

 

  LH and FSH

Interesting these seem to increase with age dramatically in both men and women according to some sources.   Now they also increase quite rapidly and to a greater extent in some salmon after reproduction inducing a quick rapid death program.

 

Surprisingly melatonin that decreases with age seems to inhibit production of LH, if I'm not mistaken, and might do similar to FSH, though haven't confirmed.    This would be in line with some of the ideas of Pierpaoli that melatonin is one the highest levels of the hormonal aspect of the aging program.

 

Bowles comments that to halt the LH FSH increase about 75mg(women) to 120mg(men) of melatonin, due to weight differences, might be necessary.

 

Melatonin seems ultrapotent against both mitochondrial theory of aging as well as against lipid peroxidation theory, as well as telomeres, and has effects on epigenetics.   Some say the cascade effects of hormones like LH FSH, may be behind the rejuvenation seen in blood dilution with albumin.  They rejuvenate probably by drastically lowering LH and FSH.   LH and FSH are rumored to in turn elicit epigenetic changes.

Edited by Castiel, 22 May 2021 - 08:00 AM.

[aribadabar]

 

 As for aging ai, yeah I suspected it wouldn't budge lower than 20 given that was the lowest age it was trained on, iirc, according to youtuber Michael Lustgarten.

 

 

You misremembered - the 20yr limitation in predicted age reduction he talked about pertained to the PhenoAge, not the Aging.AI

 

 

 

 

 Some say the cascade effects of hormones like LH FSH, may be behind the rejuvenation seen in blood dilution with albumin.  They rejuvenate probably by drastically lowering LH and FSH.   LH and FSH are rumored to in turn elicit epigenetic changes.

 

 

 Would you elaborate on the albumin-LH/FSH link?

[Castiel]

 

You misremembered - the 20yr limitation in predicted age reduction he talked about pertained to the PhenoAge, not the Aging.AI

 

 

 Would you elaborate on the albumin-LH/FSH link?

 

No he said there was a 20 year limit to phenoage, not age limit but year reduction limit, but he added more details in comments.    But in the comment sections I saw that he said lowest phenoai was trained on was 20 year olds, so that was probably max possible reduction.    Phenoai should in theory be able to reduce from 80 year old to 20 year, and he speculated the phenoage could only reduce up to 20 years so it'd be 60 years the max reduction for that particular age.    But here we tested with optimal hypothetical fake values and it seems phenoage reduces up to 9 years of age from 42 years chronological, which is 33 year drop, which surpasses what Michael suggested as a 20 year limit, also tests seem to hit a limit of 20 years of age in phenoai.     So I presume if a 100 year old somehow had optimal values, he would see his age as 9 in phenoage and as 20 in phenoai, for a total drop of 91 years in phenoage, and 80 years in phenoai.

 

If something like that happened I would need a population with similar high age, and to see not just their grimAge, but a mortality study over 5-10 year period.   Because there should be, if truly rejuvenated, a strong deviation from Gompertz law(which says mortality doubles every 7-9 years)

 

Attached is melatonin graph and Gompertz mortality graph(melatonin graph from benbest, gompertz mortality graph from wikipedia) 

Attached Thumbnails

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Edited by Castiel, 23 May 2021 - 08:02 AM.

[QuestforLife]

So I presume if a 100 year old somehow had optimal values, he would see his age as 9 in phenoage and as 20 in phenoai, for a total drop of 91 years in phenoage, and 80 years in phenoai.

No, an 100 year old wouldn't be reduced to 9 biological age in phenoAge that was just for an ~41 year old (my age in 2019). Remember that chronological age is an important factor in phenoAge (regrettably).

If I plug in the optimal blood values for an 80yo you get a phenoAge of 44.47. If I plug in the same values for a 100yo I get 62.3 PhenoAge.

30-40 years seems to be as much reduction as you can get in PhenoAge by optimising blood values. Note, this may be stretching phenoAge beyond its trained age range; it is purely going off the calculated weights of the input variables (blood values and chronological age).

Edited by QuestforLife, 23 May 2021 - 08:28 AM.

[yz69]

PhenoAge was trained on CDC's NHANES data, which is freely available for download. Just download the raw data and see what 18yo's lab results look like and optimize your numbers toward those numbers. 

[Castiel]

PhenoAge was trained on CDC's NHANES data, which is freely available for download. Just download the raw data and see what 18yo's lab results look like and optimize your numbers toward those numbers. 

 

Assuming that's true, why optimize for 18 year range when that is not lowest mortality age?    Around 12 seems to be lowest mortality age.    I know that some parameters can reach that low even in adults.

 

VLDL Increases During Aging, And Is Associated With Adverse Cardiovascular Outcomes - YouTube

 

For example look at that set on vldl per age, proper diet can bring vldl below even 15 year old mean levels.

 

Also have heard that Calorie Restriction can bring blood pressure to 10 year old level around low 100s 60s blood pressure, or something like that.

 

 

 

There have also been several cross-sectional studies investigating individuals who have practised CR over 3–15 years, compared to non-fasters. Without exception, the group practising CR had significantly lower blood pressure [8,46,47], with both SBP and DBP falling into the range found in 10-year olds [48]. https://www.ncbi.nlm...les/PMC5877612/

 

Not sure whether it's advisable to achieve such parameters.  But assuming what you're doing is healthy, at least each independent action has proven to lower mortality and increase health, and parameters don't exit normal human range, perhaps such values are not impossible to achieve with proper diet, exercise and supplements, etc

[Castiel]

No, an 100 year old wouldn't be reduced to 9 biological age in phenoAge that was just for an ~41 year old (my age in 2019). Remember that chronological age is an important factor in phenoAge (regrettably).

If I plug in the optimal blood values for an 80yo you get a phenoAge of 44.47. If I plug in the same values for a 100yo I get 62.3 PhenoAge.

30-40 years seems to be as much reduction as you can get in PhenoAge by optimising blood values. Note, this may be stretching phenoAge beyond its trained age range; it is purely going off the calculated weights of the input variables (blood values and chronological age).

Oh so it seems limit is 30 to 40 years on phenoage, then and as you say might be extrapolating outside training data.    Seems similar might apply to aging ai, but given aging ai doesn't take chronological age even a 120 year old could score an age of 20 if they somehow managed to get parameters right.

[yz69]

There are't many 12yo data in NHANES, most are 16yo and above.

[QuestforLife]

Are there any alternatives to a telomere test?

 

Telomere tests aren't widely available, especially since Covid-19, and even when they were, had numerous issues.

I had a look for any correlations between leukocyte telomere length (LTL) and other blood markers.

Two stood out: C-reactive protein and neutrophil: lymphocyte ratio (known as NLR).

 

According to this recent paper, patients admitted to hospital with Covid-19 had significantly shorter telomeres than age matched controls. 

 

 

Short telomeres increase the risk of severe COVID-19

We found a significantly higher proportion of patients with short telomeres (<10th percentile) in the COVID-19 patients as compared to the reference cohort (P<0.001). Short telomeres were associated with a higher risk of critical disease, defined as admission to intensive care unit (ICU) or death without ICU. TL was negatively correlated with C-reactive protein and neutrophil-to-lymphocyte ratio. Finally, lung tissue from patients with very short telomeres exhibit signs of senescence in structural and immune cells. Our results suggest that TL influences the severity of the disease.

https://www.aging-us...cle/104097/text

 

 

Note the reference made to the correlation between telomere length and C-reactive protein and NLR. In both cases the correlation was about -0.25. Another paper independently discovered the importance of NLR in Covid severity.

 

 

Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage

We found that NLR is a predictive factor for early-stage prediction of patients infected with COVID-19 who are likely to develop critical illness. Patients aged ≥ 50 and having an NLR ≥ 3.13 are predicted to develop critical illness, and they should thus have rapid access to an intensive care unit if necessary.

https://translationa...967-020-02374-0

 

 

 

Interestingly, this recent study into extremely long lived fish identified NRL as an important biomarker related to immune function that did not decline with age, and that was also correlated with LTL at -0.27, agreeing with the previous study.

 

 

No evidence of physiological declines with age in an extremely long‑lived fish

In this study we examined the potential relationship between age and multiple physiological systems including: stress levels, immune function, and telomere length in individuals ranging in age from 2 to 99 years old in bigmouth bufalo (Ictiobus cyprinellus), the oldest known freshwater teleost fish. Contrary to expectation, we did not find any evidence for age-related declines in these physiological systems. Instead, older fsh appeared to be less stressed and had greater immunity than younger fish, suggesting age-related improvements rather than declines in these systems.

https://doi.org/10.1...598-021-88626-5

 

 

 

This suggests immune function is essential to long life, even non-aging life, and it is closely related to telomere length in these cells, which may reflect a constant supply of progenitor cell replacements.

 

Rather like TL, NLR is an unreliable measure of aging but a robust indicator for health. For example in the following paper, NLR correlates only 0.16 with age but the average in each age category declines unequivocally, as can been seen in Table 2 (attached).

 

 

Neutrophil-to-Lymphocyte Ratio Positively Correlates to Age in Healthy Population

The eldest age group possessed the highest NLR and the youngest age group had the lowest NLR. NLR was also slightly positively associated with systolic pressure, diastolic pressure, and BMI (P < 0.001)

DOI 10.1002/jcla.21791

 

 

We can conclude that NLR varies widely for a given age, but declines reliably over a lifetime (sound familiar, anyone?).

The following paper backs up what we saw in the Covid-19 studies, indicating NLR is associated with all-cause mortality.

 

 

The neutrophil-to-lymphocyte ratio is associated with mortality in the general population: The Rotterdam Study

Inflammation is a risk factor for morbidity and mortality in the elderly. The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that integrates the information of the leukocyte differentials into one variable. We aimed to assess whether the NLR is a risk indicator for overall and cause-specific mortality in the general population. …. The NLR was higher in men, higher age categories, smokers and among individuals with lower SES, prevalent diabetes, or a history of cancer or CVD. During the 11.7 years follow-up period, 1641 individuals died. Survival among individuals in the 3rd, 4th, and 5th quintile of the NLR was significantly poorer than that of those in the 1st quintile (P < 0.001). In the multivariable analysis, NLR levels were independently and significantly associated with an increased risk of all-cause mortality (HR 1.64; 95% CI 1.44–1.86), cardiovascular mortality (HR 1.92; 95% CI 1.49–2.48), and other mortality (HR 1.86; 95% CI 1.54–2.24). No significant association was found for cancer mortality (HR 1.20; 95% CI 0.95–1.51). The NLR is a strong and independent risk indicator for mortality in the elderly population

https://link.springe...0654-018-0472-y

 

 

In many ways C-reactive protein and NLR are interchangeable, with CRP being a somewhat less useful marker, which nevertheless moves in the same direction with age and ill health.

 

 

The baseline levels and risk factors for high-sensitive C-reactive protein in Chinese healthy population

Baseline levels of serum hs-CRP are increased with ageing and are significantly higher in male than female healthy population. In addition, elevated serum levels of hs-CRP are also associated with increased SUA but decreased HDL-c and SOD. Thus, serum levels of hs-CRP may be an indicator associated with ageing in healthy Chinese population.

The multivariate linear regression analysis further identified significant correlations between hs-CRP and age (β = 0.033, P = 0.012), the levels of HDL-c (β = − 0.062, P < 0.001), SOD (β = − 0.100, P < 0.001) and SUA (β = 0.033, P = 0.015).

https://immunityagei...2979-018-0126-7

 

 

 

At this point I have more than an inkling that measures of inflammation like CRP and measures of immune function like NLR and lymphocyte % are different facets of a more fundamental aging factor.

 

Conclusions

NLR and CRP are correlated with LTL and in the absence of a telomere test may serve as a useful proxy. At a deeper level, NLR and CRP are indicators of a root cause of chronic inflammation and immune dysfunction, which may be a consequence of telomere shortening and hence the underlying aging process.

Attached Thumbnails

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[QuestforLife]

Note my 2019 blood results gave me a 1.14 for NLR (very low) and CRP was 1mg/L (reasonably low).

 

Reducing CRP t0 0.1 mg/L would have reduced my PhenoAge from 30 to 27.6.

Increasing my Lympohcyte % to 59% (there is no neutrophils field, but this assumes no increase in overall WBC) achieves a similar reduction from 30 to 27.42

Reducing them both in lock-step achieves a reduction from 30 to 24.98 yo.

 

I don't know how plausible achieving either one of these blood values is; I will have a look at the PhenoAge training data to find out.   

[Castiel]

Are there any alternatives to a telomere test?

 

 

This suggests immune function is essential to long life, even non-aging life, and it is closely related to telomere length in these cells, which may reflect a constant supply of progenitor cell replacements.

 

Rather like TL, NLR is an unreliable measure of aging but a robust indicator for health. For example in the following paper, NLR correlates only 0.16 with age but the average in each age category declines unequivocally, as can been seen in Table 2 (attached).

 

 

We can conclude that NLR varies widely for a given age, but declines reliably over a lifetime (sound familiar, anyone?).

The following paper backs up what we saw in the Covid-19 studies, indicating NLR is associated with all-cause mortality.

 

 

In many ways C-reactive protein and NLR are interchangeable, with CRP being a somewhat less useful marker, which nevertheless moves in the same direction with age and ill health.

 

At this point I have more than an inkling that measures of inflammation like CRP and measures of immune function like NLR and lymphocyte % are different facets of a more fundamental aging factor.

 

Conclusions

NLR and CRP are correlated with LTL and in the absence of a telomere test may serve as a useful proxy. At a deeper level, NLR and CRP are indicators of a root cause of chronic inflammation and immune dysfunction, which may be a consequence of telomere shortening and hence the underlying aging process.

 

https://www.research...e_of_the_animal

The thymus an important organ for immune function basically self destructs with aging, iirc, it is called thymic involution.    Years ago I had heard that high dose melatonin can reverse thymic involution but did not look more into melatonin.

 

 

Our results show that melatonin distinctly reversed the age-related thymic involution as revealed by the notable increase of cellular density, particularly the number of thymocytes, percentage of thymocytes at G2+S phases and the younger morphological appearance as a whole when compared with control animals.

https://pubmed.ncbi....h.gov/11589755/

 

Melatonin also appears to have some effect on neutrophil leukocyte ratio

 

 

The influence of melatonin on age dynamics of neutrophils and lymphocytes in blood of laboratory rats kept under different light conditions and predatory mammals--farmer silver fox, raccoon dog kept under natural light (NL) was investigated. The decrease of lymphocyte level, increase neutrophils content and alteration of neutrophils/lymphocytes ratio of aged rats (24 months) kept under natural light (NL) and standard light (LD) and adult silver foxes (2-5 years) kept under natural light in comparison with juvenile animals were detected. The reduced lymphocytes level and increased neutrophil level in rats under constant light (LL) were revealed in younger ages. The melatonin effect was detected in aged rats and adult silver foxes and not observed in juvenile animals.-[The melatonin influences on neutrophils/lymphocytes ratio of mammals blood depends on age of animals]

https://pubmed.ncbi....h.gov/23289215/

 

Can't go into scihub at the moment, but would be interesting to see what effect it had on neutrophil leukocyte ratio with advancing age, as that abstract translation doesn't seem to make it clear.

 

EDIT:
PS Was reading Jeff T Bowles melatonin book, and that guy is quite bold in self experimentation.   Seems he even took 500mg melatonin per day for a year to test it.

 

EDIT 2:

 

Googled a bit and got body of the article, seems melatonin helps prevent age related changes to leukocyte neutrophil ratio

 

Thus, regardless of the type and method of insertion, melatonin affects the increase in the lymphocytelevel and, therefore, the decrease in segmented neutrophils of adult (predatory animals) and aged animals(rats). Evidently, the photoperiod has an effect on thisphenomenon, since melatonin prevents the agerelated decrease in the lymphocyte level of laboratoryrats only under standard light (LD). The NLR of24monthold rats treated with melatonin kept understandard light (LD), as well as adult foxes kept undernatural light (NL), was near the level of young animals.It is possible that the changes observed in blood aredue to the influence of endocrine glands, in particularthe thymus, adrenal glands, and gonads, which areinvolved in the regulation of leukocytogenesis and cellular metabolism

https://www.research...e_of_the_animal

Edited by Castiel, 24 May 2021 - 02:44 PM.

[Castiel]

 

Even in healthy aging, the immune function deteriorates. That’s because, in humans, the thymus gland ages faster than the rest of the body. It reaches its peak during adolescence and begins to atrophy with a significant decrease in size and function by middle age. By 75 years, the thymus weighs only 1/6 of its maximum weight of 37 grams during youth.

Aging is inevitable and irreversible. Some age slower and live longer than others. But, sooner than later, everyone’s thymus shrinks. Declining thymus function with accompanying glandular atrophy contributes to susceptibility of infection, autoimmunity, and an increased risk for cancer.

We don’t know why the thymus gland atrophies at such an alarming rate, but aging researchers consider preventing thymic atropy pivotal in prolonging health during aging. So, it makes sense to protect your thymus starting around 35 years. And, becoming very proactive by ages 45-55.

https://drjewilliams...r-thymus-gland/

 

Edit:

 

Need to research what the dose used to reverse thymic involution in animals was,  could use that to calculate what a hypothetical dose for humans would be.   Though it remains to be seen if it'd have the same effect, some say melatonin is the oldest of all the hormones, billions of years old, and some say given its broad range of functions shouldn't even be called a hormone.

 

Edit 2:

 

Would seem like 300 mcg or 500mcg giving slightly higher than peak human blood levels might be more reasonable.  But would need to know if such low doses would stop things like thymic involution, because otherwise if megadose multi mg melatonin can seemingly do that, and it seems testing so far suggests mostly safe, then megadose it is.  As thymic involution is likely one of the strongest parts of the aging self destruct program, if you can stop or delay that especially with such a powerful broadly active substance as melatonin you're probably affecting other parts of the aging program as well.

 

Edited by Castiel, 24 May 2021 - 03:04 PM.

[QuestforLife]

Interestingly, I looked at this exact same problem before:

https://www.ncbi.nlm...pubmed/12880677

Why mess around with growth hormone when humble melatonin can regenerate the thymus, at least in mice?

I worked out this corresponds to about 14mg/day for a human; very manageable. And it wouldn't be difficult to get a metric either; lymphocyte number is a decent proxy for thymic function.

https://www.ncbi.nlm...95/#!po=35.1852

Melatonin might be able to restore the thymus with relatively small doses, and lymphocyte count is strongly correlated (~0.7) with (log of) TREC/ml, so could serve as a decent proxy for thymic function (as could NLR).

From the second reference:

T cell receptor excision circles (TREC) are present in thymocytes exiting the thymus and quantification of the most frequent of these, the δrec-ψJα rearrangement has been widely used as a measure of recent thymic function...However, TREC/ml is now considered to be more representative of thymic function than TREC/cell, especially where significant cellular proliferation occurs (e.g. during reconstitution following stem cell transplantation.

Edited by QuestforLife, 24 May 2021 - 05:43 PM.

[Castiel]

Interestingly, I looked at this exact same problem before:

Melatonin might be able to restore the thymus with relatively small doses, and lymphocyte count is strongly correlated (~0.7) with (log of) TREC/ml, so could serve as a decent proxy for thymic function (as could NLR).

From the second reference:
 

 

That sounds very good, 14mg is certainly quite low compared to Bowles speculation(75  to 120 mg), and far more reasonable to obtain cost effectively.   It still significantly higher than the usual recommended 100mcg 300mcg and 500mcg doses.    But I think it might be worth a shot.

 

Obtaining GMP and USP melatonin at that dose can be done quite cheaply.   Bowles recommended bulk powders, but I'm a bit weary of buying bulk powder from someone without multiple sources independently confirming quality of the powder.   Pill-tablet wise I was recently at Costco and saw they had melatonin on sale, not sure if local or nationwide but probably nationwide,  their 250 pill 5mg melatonin with USP seal(independent manufacturing and potency verification) was only 7.99, iirc.   Have found cheaper still in amazon, but again with something like this I need to see GMP or USP seals on the label.

 

Might also explain Pierpaoli's more limited results.   Pierpaoli gave melatonin starting at 70s to a mother in law who was diagnosed with Parkinson's, and supposedly they became Parkinson free and lived to around 102 or 104 years(dont remember the exact age).   Pierpaoli too is also pushing quite a significant age 86, still alive iirc, still not record breaking but that's at least two people with significantly higher than average lifespan on melatonin.   But I think I heard from his dosing that he recommended topping around 6mg.    He seemed to say aging was programmed, and melatonin was probably the conductor of the hormonal orchestra, but it seems he believed that was part of normal wearing down, not intentional destruction of the body that must be interfered with, so he recommended lower levels.  He commented that melatonin should allow graceful high function aging.  Others suspect the body is intentionally trying to destruct itself, and you have to intervene.

 

Bowles noted that two identical twins were diagnosed with Alzheimers at the same age, and one took 6mg melatonin while the other did not, a few years later the one taking melatonin had not progressed, while the one not taking melatonin had trouble understanding even single words.

 

edit:

Also have read that melatonin increases growth hormone, but appears to inhibit growth of certain tissues like the prostate and the breast tissue.   Also appears to inhibit cancer growth when taken at night.

Edited by Castiel, 24 May 2021 - 07:04 PM.

[Castiel]

Continuing to read Bowles book on melatonin, already read Pierpaoli's melatonin the key to life(which seems easy to find in a search engine).   Melatonin key to life talks of some of the research but doesn't go too deep in the details.

 

From what I've read it seems melatonin can stop LH and FSH rising to some extent, but I think it is not a complete halt of the increase of the age related increase in LH and FSH.   According to Bowles, it seems fasting for 5 days dramatically lowers LH and FSH.   But I think there was an article discussed on reddit that suggested too frequent long term fasts might harm the heart, iirc.    Not sure.   Still if these can knock out the LH FSH signals(which might very well be at the heart of the aging program), perhaps taking substances that protect the heart like resveratrol, and melatonin, and other compounds might negate any adverse effects from long term fasts on cardiac tissue.   It needs to be investigated.

 

Or maybe lower doses of melatonin might be more effective at reducing LH and FSH than the extreme doses Bowles tried, maybe there's a goldilocks zone of optimal melatonin intake that maximizes its antiaging benefit not too little or too much.   Will keep reading Bowles book to see what else he's found.   He commented CR increases several hormones including DHEA and melatonin, though some experiments disagree on melatonin others say it does keep melatonin high, perhaps CR too decreases LH and FSH(which Bowles too seems to suggest).

Edited by Castiel, 24 May 2021 - 08:38 PM.

[Castiel]

Was researching on melatonin and LH FSH.  So far it seems CR, and Fasting lower LH and FSH, think two days of 600 calories a week might act as a sort of  fast like effect without much issue.

 

A dose of 6mg of melatonin for a month did not alter LH and FSH

 

 

Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men

At least nocturnal production of these does not seem altered at that dose in one study, if I'm not mistaken.

Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men | Human Reproduction | Oxford Academic (oup.com)

 

Something else in the pineal gland appears to have anti LH FSH activity

 

Anti-LH and FSH Activity of Melatonin-Free Pineal Extract

Anti-LH and FSH Activity of Melatonin-Free Pineal Extract - Abstract - Neuroendocrinology 1978, Vol. 26, No. 6 - Karger Publishers

 

It is discussed in the body of the article.   Will need to check it when I get access to scihub or by googling some more.

 

A similar article discusses similar stuff regards pineal extract

 

 

The antisteroid action of the pineal gland

The antisteroid action of the pineal gland (archives-ouvertes.fr)

 

although it doesn't exactly specify what the antiLH antiFSH substance is.

 

 

 

Other studies have shown that melatonin does decrease LH

 

 

 In four subjects[postmenopausal women], they found that 3 mg melatonin at bedtime significantly decreased nocturnal LH secretion after 2 weeks.

https://www.ncbi.nlm...les/PMC1481506/

 

A dose of 500mcg had marginal statistical effects on women's LH, which I assume means smaller than 3mg.

https://www.ncbi.nlm...les/PMC1481506/

 

 

 

 Melatonin Administered in the Afternoon Decreases. Next-Day Luteinizing Hormone Levels in Men.... These data indicate that an evening melatonin administration decrease the next-day LH secretion in normal adult males without altering testosterone levels or the endogenous nocturnal melatonin secretory pattern. 

https://link.springe...385/JMN:12:1:75

 

The dose in this study was also 3mg melatonin.

 

It is conceivable that at some doses melatonin does not affect LH but at others it significantly decreases LH.    

Edited by Castiel, 25 May 2021 - 12:15 PM.

[QuestforLife]

Continuing to read Bowles book on melatonin, already read Pierpaoli's melatonin the key to life(which seems easy to find in a search engine).   Melatonin key to life talks of some of the research but doesn't go too deep in the details.

 

From what I've read it seems melatonin can stop LH and FSH rising to some extent, but I think it is not a complete halt of the increase of the age related increase in LH and FSH.   According to Bowles, it seems fasting for 5 days dramatically lowers LH and FSH.   But I think there was an article discussed on reddit that suggested too frequent long term fasts might harm the heart, iirc.    Not sure.   Still if these can knock out the LH FSH signals(which might very well be at the heart of the aging program), perhaps taking substances that protect the heart like resveratrol, and melatonin, and other compounds might negate any adverse effects from long term fasts on cardiac tissue.   It needs to be investigated.

 

Or maybe lower doses of melatonin might be more effective at reducing LH and FSH than the extreme doses Bowles tried, maybe there's a goldilocks zone of optimal melatonin intake that maximizes its antiaging benefit not too little or too much.   Will keep reading Bowles book to see what else he's found.   He commented CR increases several hormones including DHEA and melatonin, though some experiments disagree on melatonin others say it does keep melatonin high, perhaps CR too decreases LH and FSH(which Bowles too seems to suggest).

 

Melatonin is clearly a beneficial hormone that has both direct and indirect antioxidant action in additional to its sleep effects. It should be beneficial for telomeres and may have utility in regeneration of the thymus. 

 

But I've read Bowles' book and I wasn't convinced mega-dosing Melatonin has the benefits he claims, just like I don't buy his other claims that mega dosing Vit D is some sort of cure-all. I could be wrong, but if you are looking for melatonin to be a silver bullet, I think you'll be disappointed.  

[Believer]

(real) keto diet lowers androgens by about 50% due to carb restriction

also lowers igf-1

[Castiel]

Melatonin is clearly a beneficial hormone that has both direct and indirect antioxidant action in additional to its sleep effects. It should be beneficial for telomeres and may have utility in regeneration of the thymus. 

 

But I've read Bowles' book and I wasn't convinced mega-dosing Melatonin has the benefits he claims, just like I don't buy his other claims that mega dosing Vit D is some sort of cure-all. I could be wrong, but if you are looking for melatonin to be a silver bullet, I think you'll be disappointed.  

 

Yeah not sure about megadosing melatonin, at least it is good to know megadose appears safe at least for a large number of people for several years intake.

 

I'm right now wondering between either 3mg or 15 - 25mg. (btw, I think one of Pierpaoli's graph on blood levels seemed to suggest 3mg-6mg gave far less dramatic and far more reasonable blood increases in melatonin, not the extremes suggested by the other study.)   Will need to do more research on that.

 

As for vitamin D not sure how much he's exaggerating, I do know that at least in the past some recommended cod liver oil which blows way past RDA in vitamin D content(one serving of sockeye salmon also blows way past rda for vitamin d).   My grandparents took cod liver oil when young, iirc, and they also gave it to their children, I think the doctors of the time recommended they take it.   

 

Supposedly one of the claims of Bowles is that when, I think Rockefeller wanted to find more uses for oil he started promoting synthetic drugs derived from oil, and tons of hospitals were built far more per person than even now.   But people were not getting sick, so they connected it to vitamin D and started demonizing vitamin D.   Even to this day the research showing most people who got severe complications from covid were vitamin D deficient is barely mentioned, and still doubt is cast on the idea vitamin D might protect from covid complications.   That is to this day the effectiveness of vitamin D is obscured and considered suspect despite clinical evidence.(According to Bowles one source claims part of  ex President Trump's covid treatment was alternate day 50,000iu of vitamin D, barely mentioned in news.)

 

Now one of his vitamin D books is available for free at hbn, 

 

Here's the free book he gave through hbn.

edit: seems direct link to the file isn't possible, so linking to the page that has link to download free book instead.

https://hbnshow.com/...vember-21-2020/

 

You can look at his arguments, and evidence presented to see if they have merit.

 

Now he seems to have compiled a lot of anecdotal evidence on vitamin D showing great promise.   Is he exaggerating perhaps.   Personally I don't take more than 4000iu, as I've heard that's a safe threshold for D intake.   But I will check his arguments to see what he presents.(I do know higher dose D probably needs k2, and some say magnesium too.)

 

What I'm interested in checking is his Darwin book, as if it is true that both salmon and humans have age related increases in LH and FSH, that does seem highly suspicious, especially given it seems the even higher increase in salmon might be behind their quick death fast aging program.

Edited by Castiel, 25 May 2021 - 05:07 PM.

[Castiel]

An interesting note from a follow up to the interview on vitamin D that has a free ebook on D

 

 

 

Magnesium deficiency is common in our society. The RDA used to be 800 mg, but practically no one was getting that much from the food supply. And because many entitlement programs, such as Food Stamps, require that RDA amounts be obtained from food rather than from supplements, the FDA realized that giving people enough food to provide 800 mg/day of magnesium was prohibitively expensive. So they reduced the RDA to 400 mg—a triumph of politics over science.” “A few years ago the FDA proposed reducing the magnesium RDA from 400 to 200 mg. There was such an outcry about it that they backed off. Four hundred (400) milligrams is about the lowest amount an adult ought to consider taking, and most people aren’t getting even half of that in their diet.” Source: Durk Pearson and Sandy Shaw article, Putting More Power Into Your Life.-hbn

Following up Jeff Bowles’ amazing interviews - HBN Show

 

I will need to verify if that is true, but wouldn't surprise me if to safe a buck they would harm american's health.

[Castiel]

While browsing HBN, came upon the resveratrol article they had

 

Resveratrol – Astounding! - HBN Show

 

 

Resveratrol is a big problem for the practice of medicine in general because it has such a broad range of activity that it could replace many profitable drugs. In fact, drug companies are scrambling to make a synthetic version of resveratrol but it will not be nearly as good. -hbn

 

 

A very interesting read, which comments on how fraud charges for one researcher of resveratrol might have been erroneous or have been a hit job(would need more investigation to verify).

Resveratrol and Fraud (forbes.com)

An interesting snippet from the article

 

Can you find an honest doctor to conduct studies?

 

As managing partner for a company that makes a resveratrol pill I have been repeatedly advised to make our pill into a drug and spend 3 or 4 years and millions of dollars to prove it works for a narrowly defined disease. But the problem is, I don’t think eye or heart physicians could be recruited to honestly conduct these studies given their foot-dragging and denial of the evidence.

 

When the National Institutes of Health sought to determine which of two injectable eye drugs worked the best in treating wet macular degeneration, ophthalmology drug its feet for three years before recruiting patients and then took another two years to complete the study. The drug that costs $200 (Avastin) was found to work equally well as a drug (Lucentis) that costs $1500 per injection. But eye physicians often elect to use the more expensive drug, thus gouging Medicare. Eye physicians typically inject patients 6-8 times a year and earn a fee for injecting the medication into the eye. The introduction of an oral pill would take billions of dollars away from eye physicians.

 

I don’t think eye physicians or cardiologists are going to conduct any study that puts them out of business.

 

 

While HBN recommends longevinex, I think they are bit too pricy.    

 

Reading the following article it seems the original formulation was

 

 

 longevinex contains Trans resveratrol from Polygonum cuspidatum, 100 mg (micronized, microencapsulated) Quercetin 25 mg IP6 calcium phytate from rice bran 75 mg Vitamin D3, 1000 IU ferulic acid from rice bran 25 mg. Each capsule contains 303.9 mg of ingredients and considered as 100 mg longevinex (equivalent to 100 mg resveratrol) in this study.

https://www.ncbi.nlm...les/PMC3823443/

 

Well what I've done is I take these most of these ingredients separately.   Quercetin(not sure of dose but I eat lots of quercetin rich onions), Resveratrol(currently at 150mg with extra virgin geo sourced olive oil.   After I dropped my 750mg resveratrol regimen down, not sure if it was coincidental but have gotten several grey hairs after that.   Will try re upping my resveratrol to 750mg and see if it has any effect on grey hairs.   I think once in the past I had seen grey hairs whose roots had turned black, think this might have been the compound behind that, but will see when I get on a higher resveratrol regimen), D3 3000iu, and 100 mg Fisetin*(which they added in new formulation).   From time to time take IP6.   Ferulic acid will have to investigate, had forgotten longevinex had that, but I assume this and the IP6 can likely be obtained from eating nonwhite rice.

 

The longevinex resveratrol formulation claims to vastly alter gene expression even more than CR or Resveratrol, a very bold claim, which I'd need to see independent receipts to believe.

 

 

edit:

While on the topic of magnesium, it is curious if the RDA truly was 800mg and most were failing to achieve that, curious that chocolate is very rich in magnesium and top lifespan record holder was an avid chocolate eater(though chocolate also has some caffeine and theobromine as was mentioned by others earlier in the thread, also chocolate is rich in flavonols which help with circulation and brain function.)

Edited by Castiel, 25 May 2021 - 07:47 PM.

[QuestforLife]

 

Now he seems to have compiled a lot of anecdotal evidence on vitamin D showing great promise.   Is he exaggerating perhaps.   Personally I don't take more than 4000iu, as I've heard that's a safe threshold for D intake.   But I will check his arguments to see what he presents.(I do know higher dose D probably needs k2, and some say magnesium too.)

 

What I'm interested in checking is his Darwin book, as if it is true that both salmon and humans have age related increases in LH and FSH, that does seem highly suspicious, especially given it seems the even higher increase in salmon might be behind their quick death fast aging program.

 

Absolutely take more than RDA Vit D, especially as we know it (weakly) increases telomerase. I generally take 5000 IU/day, often rising 10,000 IU/day in the Winter to increase my natural immunity when daylight hours are short (make sure you also take k2 to control the calcium in the blood). 

 

But I did also try Bowles' dose of 100,000 IU/day for a while to see if it had some of the benefits he claimed, like resolving (my bad) hayfever in the Summer. It didn't work, or have any other noticeable benefits (I did solve hayfever with something else, later though). 

 

I've also read his Darwin book. He generally argues that aging is an advantage to a species, especially prey species. He is quite convincing. I am much less convinced of his interventions though. Not to say he is completely wrong about LH and FSH being bad actors, but I just wasn't convinced that was an efficient intervention point.    

[QuestforLife]

(real) keto diet lowers androgens by about 50% due to carb restriction

also lowers igf-1

 

What do you mean by real? I didn't notice any androgen drop when I was keto. 

 

I was quite disappointed by the results in my bloodwork. My triglycerides dropped a bit, and my cholesterol rocketed. I did have an awesome 6-pack. But then I basically turned into a skeleton and started losing hair and getting split nails, even supplementing biotin like mad. 

 

I didn't measure it, but I'm sure you are right and IGF-1 drops. You certainly feel that way after a while.

 

It might be possible to do keto better than I did. I was very protein heavy, probably didn't have enough fats. 

 

Later I tried a saturated fat diet (stearic acid butter, suet, that sort of thing). Even eating carbs that also made me lose significant weight. But energy levels seriously dipped and weight lifting ability plummeted. 

[Castiel]

Absolutely take more than RDA Vit D, especially as we know it (weakly) increases telomerase. I generally take 5000 IU/day, often rising 10,000 IU/day in the Winter to increase my natural immunity when daylight hours are short (make sure you also take k2 to control the calcium in the blood). 

 

But I did also try Bowles' dose of 100,000 IU/day for a while to see if it had some of the benefits he claimed, like resolving (my bad) hayfever in the Summer. It didn't work, or have any other noticeable benefits (I did solve hayfever with something else, later though). 

 

I've also read his Darwin book. He generally argues that aging is an advantage to a species, especially prey species. He is quite convincing. I am much less convinced of his interventions though. Not to say he is completely wrong about LH and FSH being bad actors, but I just wasn't convinced that was an efficient intervention point.    

 

What I asked the Pierpaoli website is if they have blood hormone data for their experiments on melatonin.   Hope they respond.    Because it is conceivable that if melatonin is the mechanism of the aging clock, LH and FSH might get significant drop or even near total stop in increase at certain doses, it might even be a drop in melatonin that triggers their increase just like it seems to be involved partly in triggering puberty too.  Melatonin is powerful stuff if taken soon after menopause can even revert menopause and restart menstrual cycle(unknown for how long.).

 

edit:

Sardi suggests Overmineralization may be behind aging, not sure I buy it,  but Pierpaoli did say Pineal gland decrease in melatonin was due to calcification of the gland, I think Sardi says lipofuscin accumulation is due to calcification of lysosomes and is reversed by chelators( like IP6 quercetin and resveratrol), arteries also get calcification.   Some snippets that do suggest there may be some degree of truth to his theory,  I'll have to research natto intake or consumers, as that has extreme amounts of k2 and should be able to help against calcification.   Do lifelong natto consumers not get calcified arteries or calcified pineal gland(aka no drop in melatonin)?  is some of CR's benefits due to reduced mineral intake?  While Sardi mentions copper and iron as other issues, so far many of these cases it seems calcium is the bigger issue.

 

 

Also got the research Sardi says suggest multiple nutraceuticals generate more gene expression changes than resveratrol alone.

 

 

 

Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart

 

An active area of aging research is focused on identifying compounds having the ability to mimic the effects of caloric restriction (CR). From 2 to 5 months of age, we fed male B6C3F(1) mice either a 40% CR diet, a control diet supplemented with a commercially available nutraceutical mixture (NCM) containing resveratrol, quercetin and inositol hexaphosphate, or a diet supplemented with an equivalent dose of chemical-grade resveratrol (RES; 1.25 mg resveratrol kg(-1) day(-1)) from 2 to 5 months of age. Cardiac gene expression profiles were generated for the three groups of treated mice and compared to age-matched control (CO) mice. All three treatments were associated with changes in several cytoskeletal maintenance pathways, suggesting that RES and NCM are able to mimic short-term CR. CR uniquely affected several immune function pathways while RES uniquely affected multiple stress response pathways. Pathway analysis revealed that NCM (but not CR or RES) regulated multiple metabolic pathways that were also changed by long-term CR, including glucose and lipid metabolism, oxidative phosphorylation and chromatin assembly. Examination of key genes and pathways affected by NCM suggests that Foxo1 is a critical upstream mediator of its actions. https://pubmed.ncbi....h.gov/18657603/

 

Haven't read the article, but it seems the compounds are quercetin, IP6 and resveratrol.    I guess one could take that through longevinex, but another way seems to be to eat some whole grain rice with some onions and some resveratrol + some olive oil perhaps to aid absorption.

Edited by Castiel, 26 May 2021 - 09:26 AM.

[Castiel]

 

excellent video on epigenetics and lifespan across species.

 

Checked the phenoage website, seems to have some blood parameters based calculation.    Think you quest mentioned something about epigenetic tests, or may be misremembering, do you know if phenoage grimage or other reputable methylation tests are available to the public?

 

edit:

 

Will say as previously mentioned IP6(inositol hexaphosphate) Quercetin and Resveratrol combo seemed to vastly alter gene expression, I presume this if true is epigenetic changes.

 

Mentioned that brown rice(whole grain rice) was a good source of IP6, and Quercetin could be obtained from onions.   While resveratrol can be obtained high quality for very cheap from various suppliers.

 

Looked at my old costco prepared meal stack, and found organic ancient grain blend, Brown Rice and Quinoa.   It comes in pouches that cook in 90 seconds in the microwave.   Incredibly it seems all the ingredients are organic(toxic pesticide free), and it has both brown rice as well as onion powder and garlic powder.

Edited by Castiel, 26 May 2021 - 11:45 AM.

[QuestforLife]

 

Sardi suggests Overmineralization may be behind aging, not sure I buy it,  but Pierpaoli did say Pineal gland decrease in melatonin was due to calcification of the gland, I think Sardi says lipofuscin accumulation is due to calcification of lysosomes and is reversed by chelators( like IP6 quercetin and resveratrol), arteries also get calcification.   

 

Over mineralisation occurs with time. But is it aging?

Glycine (and cysteine) insufficiency occurs with time. But is it aging?

Sun damage to skin occurs with time. But is it aging?

 

Totally unreferenced speculation: These things and others besides are not in fact aging at all, even if aging contributes to making them worse. I suggest that they are best termed wear and tear. The corollary to this is that we may still have to manage them even after aging is reversed. 

[Castiel]

Over mineralisation occurs with time. But is it aging?

Glycine (and cysteine) insufficiency occurs with time. But is it aging?

Sun damage to skin occurs with time. But is it aging?

 

Totally unreferenced speculation: These things and others besides are not in fact aging at all, even if aging contributes to making them worse. I suggest that they are best termed wear and tear. The corollary to this is that we may still have to manage them even after aging is reversed. 

 

Yes but we can see a path connecting it,  pineal gland overmineralizes, or calcifies, it drops melatonin levels, and probably drops other hormones as well(as pineal extract without melatonin also lowers LH and FSH), LH and FSH start rising and instructing the body to self destruct.   That's a hypothetical path connecting overmineralization to melatonin and to LH FSH theories.

 

edited previous post with some additional info.

Edited by Castiel, 26 May 2021 - 11:43 AM.

[QuestforLife]

Yes but we can see a path connecting it,  pineal gland overmineralizes, or calcifies, it drops melatonin levels, and probably drops other hormones as well(as pineal extract without melatonin also lowers LH and FSH), LH and FSH start rising and instructing the body to self destruct.   That's a hypothetical path connecting overmineralization to melatonin and to LH FSH theories.

 

edited previous post with some additional info.

 

There are many things that theoretically could be the source of aging, but most of them will turn out not to be that source and either be downstream consequences or unrelated. I personally am not convinced that the melatonin-LH/FSH link is that smoking gun. I could be wrong.

[Castiel]

BTW when it comes to vitamin D it seems the sun is best source, as it is basically free.

 

 "Sunlight can be a potent natural driver of vitamin D synthesis. A 20 minute total-body exposure (e.g., only wearing a bathing suit) to sunlight produces approximately 10,000–20,000 IU of vitamin D.2,3 This exposure is considered 1 minimal erythemal dose (MED), which is the minimum dose needed to produce pink skin coloration 24 hours after total-body sun exposure."-nordic naturals  

 

https://www.nordicna...n-to-vitamin-d/

 

If that is so a couple of hours at the beach should easily generate 50,000 to 100,000 iu for free.    Perhaps simply going to the beach a few times a month, could provide megadose vitamin D without risk(though I think it would be wise to avoid facial exposure to sun as face has lots of muscles and sun damage will result in massive wrinkling unlike the middle of a limb or the chest that basically has no major movement causing wrinkling).    I'm not sure how it is that vitamin D supplementation increases calcium, but I would presume it is by aiding absorption when taken together with calcium through the digestive track.   I assume sun exposure does not carry that risk.   Otherwise lifeguards and farmers would suffer from serious calcium issues.

Edited by Castiel, 26 May 2021 - 03:04 PM.

[pamojja]

If that is so a couple of hours at the beach should easily generate 50,000 to 100,000 iu for free.

It's downregulated with enough exposure. So no, it isn't possible to overdose vitamin D through sun-exposure. Also the abilty to synthesize it in the skin is very individual and lowers with age.

Perhaps simply going to the beach a few times a month, could provide megadose vitamin D without risk

I needed about 8.000 IU/d to keep my serum-levels at 70 ng/ml for the last 12 years. Additionally increased full-body sun-exposure up to 340 hrs per year for the last 8. Though sun-exposure did have other beneficial effects by other means, it didn't really further budge my serum levels up at all.

See the table in post 4 of this thread: https://www.longecit...nal-remissions/