38 replies to this topic

[Zarathrustra]

My daily tracking of 400+ lifestyle variables and 100+ biometrics has enabled me to adjust my life so that over the last 13 years I have improved my cardiovascular system, stabilised my chronic kidney disease, and remained in remission from my supposed terminal cancer (in 2007) for the last 6 years. I continue to by mentally and physically active at 85.

 

I follow scientifically proven ways that are known to extend average life, whilst awaiting an unequivocal biological age clock, and its subsequent application to emerging and plausible anti-ageing programs (such as CR, senolytics, and the various forms of fasting).

 

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[sensei]

Correlate your interventions to MTORC1 inhibition and inhibition of its downstream effects. If you are not inhibition mtorc1 --> start.

[Zarathrustra]

Thanks for the suggestion. However, I'm afraid I have no idea how to do that - I'm not aware how to assess my MTORC1 inhibition - I suspect I do not have that metric to hand and hence cannot do the correlations you suggest.

[sensei]

Simply look at your supplements and see if any of them are mtorC1 inhibitors.

If you practice caloric restriction or fasting then you are actually inhibiting mtorC1.

If you are taking rapamycin or a multiple of other supplements including metformin, you're inhibiting mtorc1.

[Zarathrustra]

Thanks for that elaboration.

 

I do occasionally fast for a day or two; and have taken metformin in the past - the latter correlated badly with some of my metrics for CV (raising BP) and one of my cancer metrics (Neutrophil:Lymphocytes), so I discontinued. Rapamycin I have not used.

 

I suspect inhibited mtorC1 would correlate badly for me.

 

I am cautious about unproven anti-ageing/longevity cellular approaches, as they've little track record; especially when compared with what may be called the well attested physiological ones such as resting heart rate, inflammation, etc.

[sensei]

Thanks for that elaboration.

I do occasionally fast for a day or two; and have taken metformin in the past - the latter correlated badly with some of my metrics for CV (raising BP) and one of my cancer metrics (Neutrophil:Lymphocytes), so I discontinued. Rapamycin I have not used.

I suspect inhibited mtorC1 would correlate badly for me.

I am cautious about unproven anti-ageing/longevity cellular approaches, as they've little track record; especially when compared with what may be called the well attested physiological ones such as resting heart rate, inflammation, etc.

Rapamycin and MTORC1 inhibition ameliorate:

Diabetes, heart disease, atherosclerosis, high blood pressure, reduce inflammation etc.

Google MTOR1C inhibition, MTOR1C is the proximal cause of Ageing in humans.

[Zarathrustra]

One always has to be cautious about any research findings - the results are inevitably averages; individuals may, and do, differ. I always check any such results against my own extensive database to see if it is true for me.

 

For me, metformin correlates with increases in systolic blood pressure, contrary to what you wrote. I haven't done the correlation with my HbiAC metric, but as mine is 28.8 (below 4.4 is thought to be "very good"), that too doesn't seem to be my problem. My CRP metric does show a slight negative correlation (-0.0358) with metformin, but as this metric is good for me (less than 5 mg/L) for over 4 years now (presently 1.0, that is not my problem either.

 

I do wonder what metric the various researchers used for Ageing in their work though, and how this correlates with actual aged people.

[johnhemming]

I am coming to the conclusion that there is an ongoing equilibrium involving methylation and acetylation of the epigenome.  Changes in metabolism (such as a shortage of Acetyl-coA in the nucleus) can affect where that equilibrium rests.   This can be seen in the epigenetic clocks, but in fact it is not so much a symptom purely of the state of the epigenome, but in fact a system of the status of the aggregate health of the mitochondria particularly, but other aspects of the cell and the state of the epigenome.

 

Hence there are lots of different ways of improving the dynamic metabolic balance of the cell.  Those will be reflected in the epigenome, but it is partially a symptom as well as being a cause.

[Zarathrustra]

Seems right. Which is why I stick with the macro and well-attested/scientifically proven ones both for the metrics and improving them (such as walking, HIIT, deep sleep for improving resting heart rate). I'd be worried if, say, the cell-based age metrics indicated I was getting younger whilst my resting heart rate increased.

[johnhemming]

I think you are right to keep a solid eye on basic metrics like resting heart rate and BP.  I have been very pleased with the information available from the continuous glucose monitor.  More recently I have taken to walking really quickly to get around rather than necessarily doing any running or going to the gym.  It does take my heart rate up quite high and it is interesting to see the blood glucose drop initially then pick up.  Hence I do exercise as part of just walking to my office.

 

 

[sensei]

Rapamycin retards epigenetic ageing of keratinocytes independently of its effects on replicative senescence, proliferation and differentiation

"We report here that epigenetic ageing is not affected by replicative senescence, telomere length, somatic cell differentiation, cellular proliferation rate or frequency. It is instead retarded by rapamycin, the potent inhibitor of the mTOR complex which governs many pathways relating to cellular metabolism."



https://www.ncbi.nlm...les/PMC6555449/

[Zarathrustra]

Re Birmingham Guest: I concur. There is a lot of evidence that the more walking one does per day, the longer one lives. I add to my 14K/day with HIIT and pressups.

 

Re Guest 2: Thanks for that link. Rapamycin does appear to be one of the better anti-ageing supplements; tho' I understand it needs a cooperative GP to obtain it. I note that usage seems to be beneficial for all three of my morbidities (CV, CKD, and cancer).

 

I made a mistake in my earlier response to you, with regards to Hb1AC - I do indeed correlate it with each of my 400+ lifestyle variables (I use it as a CV metric). Interestingly, it is one of my metrics that correlates improving as I age.

[johnhemming]

"We report here that epigenetic ageing is not affected by replicative senescence, telomere length, somatic cell differentiation, cellular proliferation rate or frequency. It is instead retarded by rapamycin, the potent inhibitor of the mTOR complex which governs many pathways relating to cellular metabolism."
 

 

The question is in a sense a semantic one, but it has a real significance.   The question is what is at the core of ageing.  The reason it matters is that guides best as to how to deal with it.

 

The deterioration of mitochondria is in part caused by oxidative stress.  This then links to problems with the epigenome.  The systems to deal with senescent cells fail.   What I would suggest is that ageing is a sum of those systems.   Hence we need to put in protocols that deal with all of that.  Obviously inhibiting mTOR enables some of the corrective systems to operate.   It would not, however, be a full solution unless there is some action to ensure optimal levels of protection against Oxidative stress.  New mitochondria will be in a better state, but if they deteriorate quickly through oxidative stress then the same problems with a shortage of Acetyl-CoA for acetylation remain.

[Zarathrustra]

I agree in the sense that we need to look at both aspects at the same time - the overall health of a person, following the long-attested science (such as walking a lot increases living longer; not being obese) - not least so one is alive long enough to be around when the cellular level interventions are sufficiently proven to be incorporated into one's lifestyle.

 

I also agree that it is plausible that ageing is due to a sort of summation of what is happening over the whole biome's cells, tho' I wonder at the inter-related-ness of the whole rather than the summation of the cells directly may be as important. An extreme example is cancer - the cells are doing fine, multiplying away, but the body is not.

 

As long as one is using the known life-extending science (exercise, diet, sleep, etc) to function well and with increased chances of living longer, and then cautiously perhaps adopting/incorporating cellular enhancements once sufficiently tested (such as autophagy), then this may be the best we can hope for nowadays.

 

To my mind, there is still much uncertainty about proposed cellular interventions, whereas there is virtually none about the whole-body ones (such as exercising - which anyway is thought to improve the mitochondria).

 

 

[sensei]

All interventions are cellular at the end of the day.

Furthermore, exercise promotes longevity through MTOR inhibition, induction of AUTOPHAGY in muscles (including the heart) and subsequent STEM CELL release.

Unfortunately, exercise does not cause as profound SYSTEMIC AUTOPHAGY, as does PROLONGED FASTING, DRASTIC CALORIC RESTRICTION, or RAPAMYCIN. Nor does exercise remodel the immune system, or inhibit the inflammasome, or reduce inflammatory cytokines, or release stem cells - to the degree of other types of MTOR inhibition.



(emphasis only, not shouting)

[johnhemming]

To my mind, there is still much uncertainty about proposed cellular interventions, whereas there is virtually none about the whole-body ones (such as exercising - which anyway is thought to improve the mitochondria).

 

My view about certainty is that I look at the question as to what harm can be done by an intervention and what merits there may be.  I aim to measure where possible the effects on myself.  I expect different people to be affected in different ways.

 

If  there is something where there is a reasonably good chance an intervention will help with health then as long as it is not likely to cause harm I think it is worth giving it a shot.  I do, however, aim to see if I can isolate out an effect.  Hence I am trying things like Varioxia and Molecular Hydrogen as well as a number of small molecules.  I do have reasonably good personal evidence for a number of things, but as I get a better idea what we are trying to do (viz improve cellular health so that cells function properly) it is easier to hunt down the right research information and fill in gaps by inference.

[sensei]

I expect different people to be affected in different ways.

Respectfully, Why?

Except for few outliers and controlling for allergic/anaphylactic incidents,

- drugs act THE SAME WAY on humans with only small differences, usually based on dose/response.

One should EXPECT for interventions seen to promote longevity in a human to WORK EFFECTIVELY for the VAST MAJORITY of humans.

If biochemistry worked differently, we would not have the pharmaceutical industry.

Mathematically, one would expect GENERALIZED FAILURE of an identified longevity promoting treatment that worked in a human or in a group of humans, to be a 4+ sigma outlier.

[johnhemming]

- drugs act THE SAME WAY on humans with only small differences, usually based on dose/response.
 

 

We probably don't disagree on this.  Because people have different starting positions then the effect of various molecules will differ.

 

For example if someone is deficient in Vitamin D then supplementing will have more of an effect.

 

The underlying chemistry remains the same.

 

People will also have different genetic make up and at times that may be relevant.

 

In particular if the target is improving mitochondrial health if someone uses multiple molecules each to achieve the same objective they are likely to find diminishing returns.

 

So I have supplemental melatonin and also I have an IR radiation device.  Both target mitochondrial melatonin.  I may try to measure one in isolation of the other, but it is complex.

I would add a point that some research is really dreadfully defined.  I saw a Vitamin D study which involved giving a monthly large dose rather than smaller daily doses.  That is a ludicrous thing to do if people understand anything about vitamin D metabolism.  However, the results of that study get carried forward into reviews.

[Zarathrustra]

Thank you Sensei and John Hemming for responding/contributing to my posts. I will attempt to address the last four since I last contributed - but maybe not in order; please bear with me. But feel free to skip this if it is too long or seems to miss your points.

 

People do differ, oft-times in quite widely disparate ways. I recall a small TV experiment in which half-a-dozen or so volunteers were fed identical nutrition for a few days. The results were very different - a couple did not alter their body composition whilst all the others did, some quite significantly. One of the reasons I started self-tracking was I suspected that the received wisdom at the time might not apply to me - and it didn't. The plausible reasons are many, but the main lesson was that only by self-tracking could I be sure what worked for me. I have since read many seemingly expert people quoting apparent good research make different recommendations - high-fat, low fat; no animal fat, lots of animal fat; low carb/high carb. etc. I emphatically do not agree that all drugs work similarly for all people within a narrow range of variability. One gaping hole in this theory is that most drugs are trialled on young white males - not females; not the old; not children (yet then prescribed for all and sundry). On top of that, there is indeed often wide variability in the tested group. It gets worse, as recently reported (but known for some time, see long history of poor research and fraud - not just the Sacklers but Ancel Keys, the tobacco and sugar lobbies work, and books such as Wrong by David Freedman, Devra Davis' The Secret History of the War on Cancer. I could go on, but with this long history of bad research, fraud, and poor research, I am surprised by your surprise. Having said all that, I note that you too are aware of some shortcomings of some research.

 

My own tracking shows that for me, how much I eat hardly matters - it is the type of food I eat that matters. Similarly, exercise hardly changes my body composition; it is nutrition that does. Oddly, exercise correlates with reduced muscle-mass for me. I cannot explain that, it is just so.

 

As regards supplements, I judge them by how they correlate with all my metrics. I may decide to take any particular one because there’s been some plausible explanation of how it may help me, but then find it correlates badly on my metrics -such as MitoQ and Niacel. Hence my caution on arguments for ideas on such supplements to help by interfering with my mitochondria. I’ve had similarly mixed results for melatonin.

 

Re Sensei: I'm not sure it is correct to say everything is in the end cellular - the body's system is more than the sum of its parts. And what may be good for some parts may not be good for others too. For instance, exercise is good for CV and cancer, but not for kidneys - as it generates creatine, which is bad for kidneys. So I have to make a judgement as to how much exercise I do. Another aspect is that of body fat - we now know that being somewhat overweight seems to enhanced longevity even to' other cellular evidence is that too many fat cells seem bad. This is further underlined by obese people surviving surgery better than the less obese. It may be of interest that when I was considered terminally ill with cancer, it was body fat that was depleted, not muscle – maybe with that fat I would not have made it.

 

For me, CR is maybe not a good way to longevity – because of the evidence that being somewhat overweight correlates with living longer, and I found it just too difficult.

 

Overall, my main point is that we have decades of research indicating that such things as walking, the Mediterranean diet, good sleep, good oral hygiene, not smoking or drinking alcohol, etc correlates with living longer. None of the proposed new interventions, plausible tho’ they may be and indeed have short-term research supporting  them, have this track record. As, hopefully, evidence mounts for some as being indeed life-extending or age-reversing, then I think relying on the more macro work in my own lifestyle will enable me to still be alive to adopt them.

 

[johnhemming]

I have a lot to agree with in Zarathrustras post.  I must admit I am quite drunk at the moment because my own protocol does include quite a bit of alcohol from time to time.

 

In the end, however, the health of the non cancerous cells drives the health of the organism.   The variation in responses between individuals is fact specific not a variation in the scientific laws. Everything is in the end cellular, but there are responses between cells.

 

 

[sensei]

Be careful that you are not conflating BMI with excess adipose tissue.

While the lowest BMI may have a signal that does not enhance longevity, what YOU call a little overweight as measured by BMI does not directly correlate to EXTRA ADIPOSE TISSUE.

Mathematically, it is MORE LIKELY, increased BMI is due to increased MUSCLE MASS, considering the KNOWN METABOLIC ISSUES associated with excess fat.

As an example, I had 8% body fat, but weighed 187 lbs at 5'10 at age 35.

That makes me Overweight with a BMI of 26.8.

Edited by sensei, 04 February 2022 - 07:51 PM.

[Zarathrustra]

I’m rambling here, but thought I’d share my  thoughts on the last two responses. I’ll not mind if this is ignored – it is lengthy.

 

John Hemming: Thanks. Hope you’re well and no hangover.

 

I’m not sure what to make of “The variation in responses between individuals is fact specific not a variation in the scientific laws”. It is because I accept cause-and-effect works from the cellular level up (we’ll leave out the oddness of quantum-ness) that the individual needs to check the research, which is based on a peculiar few, needs to be checked for oneself.

 

Whilst I accept what happens at the cellular level may underlie much of illness/health/longevity, it cannot be the whole picture – as I’ve said, the system is more than the sum of the bits. At one extreme, an extreme accident overrides all cellular events; interactions of organs likewise. But more importantly, we cannot know what is happening at the cellular levels. What we do know is the more macro events such as BP, etc. And the state of these metrics is the basis for lifestyle action. Even blood assays have to be translated into lifestyle actions  - changes of diet, etc.

 

I’m not sure of the whole basis of developing an ageing marker based on cellular data. I understand the idea – find some cellular metric (methylation, telomere length, etc) – and measure it on a random sample of different aged people and see if there’s a consistent change related to their chronological age. Then if older people have the same measurement as an younger person, they are biologically younger, and visa versa. The track record of such attempts to date is that the various markers do not agree. Plus we do not yet have a long enough time to know if any such metric equates with lifespan. Then there’s the question of individual variation – so a person found to be older may not die earlier than one found younger. Just not yet known. Meanwhile, we do have had data over decades of such things as inflammation, resting heart rate, eGFR, average steps/day, grip strength. So whilst awaiting both ageing markers and interventions such as CR, rapamycin, being shown to give longevity, perhaps best base my lifestyle on these older established interventions.

 

Sensei: Whilst I agree that BMI is a poor indicator of body fat (waist:height is better), it is used widely and, tho’ not good, is better than nothing. Based on BMI, 2.8 million Britons were followed and those who were BMI 25-29.9 were 20% less likely to die than those of 18.5-24.9, and even those with BMI 30-34.9 were 10% less likely to die. Having said that, such people were prone to more diseases than the ‘normal’ ones. The British Heart Foundation’s research analysed 401,000 people who underwent heart surgery: 4.4% of normal people died; 2.8% died who were overweight; and 2.7% died who were obese. Heavily muscled people who have high BMI are, I suspect, an insignificant minority within the aforementioned researched peoples. No doubt the researchers were alive to such problems too. So my caution about CR stands. However, given the number of adherents CR has, hopefully the data will come in about their longevity – but as yet, it is just a plausible theory and is countered by the above hard data.

 

I hope someone is keeping a database of some of the CR people to both check their longevity and how their biometrics are stacking up.

 

[sensei]

@ Z

You may find it interesting that 180lbs at 5'10" is overweight per a 25.8 BMI, and I don't think anyone would consider that highly muscled.

As another example, Wayne Rooney was 183lbs when he played, at 5'9" his BMI is 27 putting him in the middle of overweight.

I'm 5'10. In order to be " healthy " per BMI, I have to weigh between 125 and 169 lbs. If you choose the middle 147 lbs as healthy, I would look emaciated. I know from experience, I tried vegetarianism 27 years ago when I was 23. I weighed 145 lbs, looked sick and emaciated and felt weak and ill

Edited by sensei, 06 February 2022 - 12:35 AM.

[Zarathrustra]

Thanks Sensei.

 

Interesting examples that underline the need to move on from BMI as a metric for excess body fat, but I don't think the outliers invalidate the research data that being somewhat overweight, especially in the elderly, is in some way conducive to longevity and that being normal may not be best.

 

Perhaps more importantly, such research indicates that CR followers perhaps need to be careful that they do not lower their body fat too much.

Edited by Zarathrustra, 06 February 2022 - 08:30 AM.

[johnhemming]

Sensei and Zarathrustra:  I accept that BMI does at some times indicate people are overweight when they are not.  It has the advantage of being relatively easy to calculate and there is no need in calculating it to distinguish between heavily muscled people and those who have a lot of fat.  That is why it continues to be used.  Over time it might be that people look also at body density or simply adjust it for weight.

 

Zarathrustra; I accept that the macro measurements matter.  However, when it comes to "ageing" at the cellular level it is quite clear that this happens as a result of the failure of the body's systems to operate properly.  The research into the Citrate Carrier elicited a very clear biochemical basis for osteoporosis and links it in part to deterioration at the mitochondrial level through Oxidative stress.

 

The Epigenetic age is a mechanism for measuring the level of disorder in the Epigenome.  Whether that disorder is as a result of some generalised breakdown of cellular health (which I think it is) or whether it is actually a pointer set at the wrong point does not really matter in that either makes it a useful measurement.

 

The question being asked, of course, is whether Epigenetic age can be seen in health indicators at the macro level.

 

The failure of the sirtuins to properly maintain the Epigenome can be seen to follow from a shortage of NAD that can be seen to follow from excess inflammation causing the cellular defences to concentrate resources on short term problem.  The growth in inflammation can be seen to develop from mitchondrial difficulties caused by Oxidative Stress.

 

This gives a good theoretical basis upon which improving the handling of reactive oxygen species reduces inflammation and then acts to make certain diseases (cancer, diabetes, CVD) less likely.

 

In my own N of 1 experimentation I can say with evidence that my macro health has improved.  I have lost about 1/3 of my body weight which was mainly fat being lost.  My resting heart rate came down to the mid 50s and my blood pressure into a good range.  Historically I had intermittent angina and no longer have that or indigestion.  Even when I drink quite a lot I don't really have a hangover (I don't have one now).  I also have lost some warts which were hanging around.  I have got one result for Epigenetic age which was 54 (I am 61) and they said the chronological age for people with that epigenetic age was normally 52 (I am in the process of testing out two other clocks).  I have even had a few dark hairs grow on my scalp where I have not had hair for about 15 years.  Sadly I did not measure my high frequency hearing range at the start of the process.  This I think is a useful measure because it shows the health of the specialised hair cells in the cochlea.  I can currently hear up to 14kHz which implies my cochlear cells are in a better state than the average person of 61.

 

My conclusion is that my macro health has improved primarily because of improving the health of my cells at the cellular level and particularly through reducing oxidative stress (with its knock on effects as above).   Obviously I am 2/3 of the person I used to be and that is quite a big change, but although that could be seen as to affect blood pressure I don't think it could affect hair either in my ears or on my scalp.  Hence my conclusion is that the bigger shifts in my health come from improving the function of the cells at a cellular level.  

 

Hence I have two key conclusions:

a) Epigenetic age is a measure of cellular health in the round and getting a reduction in epigenetic age will indicate an improvement in health at the cellular level.

b) An improved cellular health has happened for me personally on the basis of the protocols I am following which has also resulted in an improvement of health at the macro level.

 

[johnhemming]

Interesting examples that underline the need to move on from BMI as a metric for excess body fat, but I don't think the outliers invalidate the research data that being somewhat overweight, especially in the elderly, is in some way conducive to longevity and that being normal may not be best.

 

Perhaps more importantly, such research indicates that CR followers perhaps need to be careful that they do not lower their body fat too much.

 

Its an interesting question.  In a sense this sort of research demonstrates the difficulty of measuring systems with multiple input variables to get a conclusion for a single input variable.

 

My personal view on this is that as people get older at times it is useful to have some reserves of fat to deal with situations when other parts of the system break down.  However, it is probably actually the level of blood sugar that is more important than actually fat when you get into a reasonable range and the research you refer to probably does not apply to all categories of people purely based upon age.

 

When i was obese that put a lot more pressure on my joints than now and I don't myself think there is an argument for obesity.    However, I do accept the point that there is nothing magic about the 25 BMI threshold.

[sensei]

Aactually, extra adipose tissue seems to be responsible for chronic inflammation.

"Along with its production of specialized adipokines, adipose tissue also secretes proinflammatory cytokines that likely contributes to the low-level systemic inflammation that has become a hallmark of various metabolic syndrome-associated chronic pathologies"

https://www.intechop.../chapters/68495

[Zarathrustra]

Thanks John. You’ve done well.  May all your signs continue to improve – with that track record, I’d continue doing what your do. However, my own metrics, macro and micro, are somewhat different – perhaps because I’m older at 85.

 

I tend to see things upside down to you. My micro must be good if my macro is.

 

I’ve tried various anti-ageing supplements over the years, with mixed results. Some seem to help, some help with, say, CV, but be bad for others, such as cancer. Niacel and MitoQ correlate badly for CV for me.

 

I’m with you on the CR issue.

 

As my inflammation, Hb1AC, and resting HR are all good, along with BP thanks to HT pills, I’m presently just needing to concentrate on getting my kidney better.

 

Thanks too to Sensei. Your point re adipose tissue makes sense. My own data shows a reasonable correlation between inflammation and body fat (about 0.65) over 14 years. Tho’ as I presently have about 21% fat, I seem fortunate to only have 1 mg/L CRP levels – perhaps a reflection of the predominantly vegetarian diet and the curcumin I take.

 

[johnhemming]

The difficulty is measuring things at the microscopic level.  Knowing the state of Oxidation of the Citrate Carrier is doing to be difficult.  We can now get NAD levels (which I think is all part of this although i think a consequence rather than a primary cause.  That is not to say that supplementing with NAD boosters is not a good idea, it obviously is.  However, reducing inflammation should increase NAD availability.

 

I think in the end a lot of the aged based deterioration of cellular metabolism can be considered to be a single system although there are particular ways to improve certain things.

 

[sensei]

The difficulty is measuring things at the microscopic level. Knowing the state of Oxidation of the Citrate Carrier is doing to be difficult. We can now get NAD levels (which I think is all part of this although i think a consequence rather than a primary cause. That is not to say that supplementing with NAD boosters is not a good idea, it obviously is. However, reducing inflammation should increase NAD availability.

I think in the end a lot of the aged based deterioration of cellular metabolism can be considered to be a single system although there are particular ways to improve certain things.

I don't think you have to worry overly much about oxidative issues -- as long as you are regularly inducing and enhancing AUTOPHAGY.

@Z

I would caution using CRP as the only measure of inflammation.

The NLRP3 inflammasome is the adipose tissue associated culprit - it causes IL-1B, IL-18 release which are highly inflammatory and instigate multiple downstream cytokines including IL-6 and IL-17.