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Suddenly became curious if there is something like "assembled picture" of general health from the "non-successfull aging perspective".

I do not like "pure synthetic" things like "clocks" and so on, because I suspect these are designed rather to be sold as actuary tool rather to be used as a personal strategy/guidance tool so I thought about frailty as a potential candidate for being such an angle and pre-frailty seems a keyword that can help find e.g. this:

Identifying the Biomarker Profile of Pre-Frail and Frail People: A Cross-Sectional Analysis from UK Biobank



Methods: In total, 202,537 participants (67.8% women, aged 37 to 73 years) were included in this cross-sectional analysis. Further, 31 biomarkers were investigated in this study. Frailty was defined using a modified version of the Frailty Phenotype.



In contrast, our findings identified that both pre-frailty and frailty were also associated with lower levels of apoA1, total, LDL, and HDL cholesterol, albumin, eGFRcys, vitamin D, total bilirubin, apoB, and testosterone in women and men. Lower calcium, total protein, and IGF-1 concentrations were observed in pre-frail women and frail women and men; low creatinine levels in both pre-frail men and women and frail women, while lower AST levels were found in pre-frail and frail men.

A bit surprising at a first glance because it contradicts with often recommended to have ldl/apob the lowest but concordance of albumin+testosterone+ca+igf1 and lipids except tg allows to make a guess - their data already includes older people that are undernourished because of natural reasons, so just less building blocks for the molecules and at the same time - less energy for feel good and so on.

My own igf1+sexhormones are low while albumine is upper norm but I think it is rather a combo of middle age and a protein(structure)/calories(nett) limits caused by diet/regimen, Ca and vitD are on supplemental strategy, thus out of scope).

Anyway, study could be useful to contribute to the picture, especially when it is going about people that are not on a specially crafted diet and lifestyle.





Edited by IgorF
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19 hours ago, IgorF said:

A bit surprising at a first glance because it contradicts with often recommended to have ldl/apob the lowest

Matches my experience as someone with SBMA aka Kennedy's disease who became very frail in my late 40s with LDL in the range of 120-140.  But after many lifestyle adjustments pursuing health and fitness I am doing much better at 58 with TC now over 500.   I'm fairly confident I will continue making improvements in body composition and fitness and think TC over 600 is likely and 700 is possible for me.  Curiously the evidence that androgens are essential to the pathology of SBMA is far stronger than the evidence linking cholesterol to heart disease and my androgens have risen proportionally with my increases in cholesterol and are now double to triple their reference ranges but yet my SBMA symptoms are a fraction of what they were.

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3 hours ago, Todd Allen said:

my androgens have risen proportionally with my increases in cholesterol

AFAIR, chole is a building block for them, thus - having more precursor seems makes it more likely for it to be "pressured out" that pathway.

Your case is so unusual to be analized that I can't draw a conclusion about desirability of having the hormones high but in any case, they are high in much more natural way, with all the signaling networks involved than just artificial injection or plaster with testo like many "health and wellbeing" providers do.

I also suspect that higher level of these things is a significant part of feeling better.

The only thing I could be curious/concern - free testo, there is a hypothesis (or maybe a theory) that our best scenario is to have testo at the most close level to the amount of receptors it binds to. If there will be much more of free testo it will be either "disarmed" with binding protein or it will do unwanted things, but I think these areas are not studied wide enough, especially for dietary tweak that changes the things as a whole.





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On 5/7/2023 at 2:56 PM, IgorF said:

pre-frailty and frailty were also associated with lower levels of apoA1, total, LDL, and HDL cholesterol  [ETC.]

  Causal explanations are required.   For example:


Lower concentrations of total, LDL, and HDL cholesterol, as well as higher triglyceride levels, were associated with frailty in previous studies [16,35,49]. These findings were also reported in our study among pre-frail and frail people.

Even if these results may be surprising, changes in plasma lipid levels are well-known in the acute-phase response or are associated with malnutrition [50]. Both conditions could be presented in pre-frail and frailty people.


Lipoprotein (a)  is an interesting case.  


...our study reported that lipoprotein A was only significantly related to frail women. Consistent with our findings, another study confirmed that elevated lipoprotein A concentration was not associated with an increased risk of coronary artery disease in a population over 65 years [53].

Lp(a) has been identified as a  super-dangerous  causal risk factor for cardiovascular disease, and pharmaceutical companies are going all out to develop drugs that reduce it (statins are ineffective).   Nevertheless, Lp(a) may have anti-infection and anti-cancer functions (perhaps especially if combined with exercise), and  may actually be a double-edged sword.

Edited by Sibiriak
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4 hours ago, Sibiriak said:

Causal explanations are required. 

Well, the angle of view is rather - to see how the "whole edifice" of cheap markers moves when people are diagnosed with frailty. The absolute values in their table are not dramatically different.


If someone wants to use ascvd as an angle then much more precise data should be picked, e.g.:

- tg is big enough to indicate regular energy surplus

- tg is big enough to be assessed as a separate risk (it _seems_ atherogenic _sometimes_ on its own, not as an indicator of cargo delivery units)

(tg increase due to alcohol consumption and keto diet should be cut off, for the widely used risk models to have sense)

- concordancy of ldl-c and apob (all 4 combos are different from assessment perspective if I understand the things right) if apob is bigger than 85 (studies from 70-90s, or even less as now are being discussed)

- lp(a) together with already listed above things if it is bigger than let's say "good values"

- glucose-related stuff - it seems it could contribute to molecules that are bridging atherogenic particles and walls but hard to say about degree

- all the things above - if other ascvd risks are already present will become even "tighter" quantitatively

So even without trying to answer the recent question - if we have to cut off apob risk completely (thus lp(a) also?) with a lifelong drug there is enough moving parts to make it impossible to answer simply what strategy to choose in what particular case - there are plethora of explanations that will support any chosen one.


But getting back to frailty topic - I am interested in some way to assess its upcoming early, hoping it is correctable. The reasons are

- there are people that look and perform good for a long time, then suddenly, in months their look changes to the frail phenotype. When it happens after 80 it is expected but sometime it happens earlier and I hope there will be some tool to try to predict and modify this

- age frailty could often be preceeded or superseeded by a major event like stroke, thus it is not about just gradual quality of life decrease





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14 hours ago, IgorF said:

AFAIR, chole is a building block for them, thus - having more precursor seems makes it more likely for it to be "pressured out" that pathway.

In my case I don't think high cholesterol is driving increasing androgens but rather it is allowing it.  10 years ago when my health was poor my androgens were around the top of their reference ranges while the precursor DHEA was at the bottom.  Since then my DHEA has been in the middle of its range.  If rising cholesterol was pushing androgens higher I'd expect DHEA to also go high.

14 hours ago, IgorF said:

I also suspect that higher level of these things is a significant part of feeling better.

Probably, although I think the mutation in my androgen receptor diminishes the effects of androgens and they are rising in compensation or rather because there is insufficient signaling to suppress further demand for production.  I expect androgens will stop rising if/when I achieve a normal degree of androgen signaling.  I probably have experienced more profound effects due to estradiol and perhaps estrone both of which have also risen fairly proportionally to my cholesterol and androgens and are likewise between double and triple their reference ranges.  I have indications my estrogen signaling is strong such as very high EPA despite no supplementation and very gynoid fat distribution both of which are associated with reduced CVD risk.

14 hours ago, IgorF said:

If there will be much more of free testo it will be either "disarmed" with binding protein or it will do unwanted things, but I think these areas are not studied wide enough, especially for dietary tweak that changes the things as a whole.

Early on my free T and DHT were lagging the increase in total T but lately they have been outpacing it although so far my endocrinologist has found no indications of the harms typically encountered by men using exogenous androgens for levels approaching mine.  He is most concerned for changes in RBCs and heart structure and function and has given no explanation for why I have not developed those issues or if/when I might.  My increase in estradiol has been strongly correlated to free T and I would like to moderate it.  I hope achieving very low body fat will significantly reduce the ratio of estradiol to free T but further progress has become challenging and slow.

My concern for cholesterol driving CVD is perhaps inordinately low but I think concerns for cholesterol are similar to those regarding BMI.  Population level statistics for each find correlation between higher levels and adverse outcomes.  The commonness of obesity likely causes the adverse correlation with higher BMI but yet on an individual level changes in bone and muscle mass can run completely counter to the correlation between change in BMI and health or longevity.  For cholesterol I suspect the correlation is heavily biased by the modest rise in LDL and larger rise in apo B associated with metabolic syndrome.  The vastly higher rises in cholesterol seen in hibernating bears, migrating birds and people such as myself becoming lean on very carbohydrate restricted diets I expect are due to completely normal healthful physiological processes and as different from the extremely common small rise in LDL with metabolic syndrome as is the change in BMI due to fat vs muscle mass.

Edited by Todd Allen
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15 hours ago, Sibiriak said:

Lp(a) has been identified as a  super-dangerous causal risk factor for cardiovascular disease, and pharmaceutical companies are going all out to develop drugs that reduce it (statins are ineffective).

We have also been told that Lp(a) is largely driven by genetics and even more static than cholesterol levels and thus limited testing is sufficient to identify risk and the need for pharma based treatment.  Here is a different message which despite being based in part on n=1 ie anecdotal data I find interesting and potentially more compelling because it comes from curiosity versus all of the data coming from a desire to create and sell drugs for profit.


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8 hours ago, Todd Allen said:

We have also been told that Lp(a) is largely driven by genetics....

True, but  there are definitely a number of non-genetic factors noted in mainstream medical research ( and few not so noted).  For example, saturated fat intake vs carbohydrates.

Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement (October, 2022)


Table 1          Non-genetic influences on lipoprotein(a) concentration

Condition/intervention                                                                                                Effect on Lp(a) levels

Replacement of dietary saturated fat with carbohydrate or unsaturated fat        ∼10%–15% increase 

Low carbohydrate diet high in saturated fat                                                                          ∼15% decrease 




Edited by Sibiriak
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Protein intake (if not obviously inadequate) seems is not indicating coming frailty

Protein Intake and Frailty in Older Adults: A Systematic Review and Meta-Analysis of Observational Studies



Our pooled analysis indicates that protein intake, whether absolute, adjusted, or
relative to total energy intake, is not significantly associated with frailty in older adults.
However, we observed that frail older adults consumed significantly less animal protein
than their robust counterparts. No significant differences in frailty status were observed
according to the amount of vegetal protein consumed. These findings indicate that protein
sources might have a key role in the development of frailty. Furthermore, a higher protein
consumption is longitudinally associated with a lower risk of frailty.

And seems confirms already spoken (including these forums) hypothesys - older adults could benefit from animal protein sources, hard to say if vegetable sources with proteins attached to fibers will bring them the same availability if they will be just quantitatively increased.

In any case - no protein obsession, (e.g. 2g per pound and so on) is needed to just "do as others and fit into the stat".



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Probably I've missed something but... If frailty by the simplest of definitions means weak bones and hypotrophic appendicular lean mass (small and weak muscles), then any considerations should be limited to sedentary people (including the disables ones, who cannot exercise).

Otherwise a moderate exercise is usually enough to overcome frailty, would those parameters oppose so strongly to the decisive signals of hypertrophy bestowed by exercise?


Edited by mccoy
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I remember in some book on geriatry an allusion to a famous phrase about pornography - it is hard to make a definition of what it is but we all know it when we see it.

In the articles and books there are 2-3 of 5 or more:

- unintentional weight loss

- selfreported fatigue

- diminished physical activity

- grip strength (more for males)

- movement speed

are usually mentioned that frailty could be diagnosed.

Pre-frailty thus is when 1-2 of these are having place and can not be attributed clearly to another more narrow known medical condition.


I personally think this set of things when carefully distinguished will definitely divide those who are aging in accordance with biological capacities and those who is not. 80% of them.


If imagined in Venn diagrams pre-frail and frail people will not cover the same manifold as metabolically deceased and so on, but a large overlap will have its place. For frailty in older age if it is not a consequence of something accute I think it is a sign of the main driver of aging according to Nick Lane - mitochondrias are doing respiration-related biochemistry worse and worse. Those who are lucky to have better tuned mitochondrias to their own genome will have this condition very close to their biological maximum but we are not all so lucky. I also (at least now) think that this mitochondria-to-host tuning is really a biggest gift that mother's biology makes for a children and because it relies on wide pseudo-random process (maybe stupid definition) we do not all live long, just very rare ones are.

Frailty often comes on its own but also severe health challenges will often produce such a condition and it will in many cases be irreversible. And vice versa - frail people are at higher risks from many perspectives.

Frailty is often out of scope when people are talking about lifestyle related things, accute things are draining more attention but we definitely do not want them also.

Another aspect, less described in modern books - self-induced frailty, getting closer to the topics of this forum - with intentionally pushing self to the limits. While I have nothing against doing it for whatever reason, I think having some sympthoms from this list in a set is a possible signal of overdoing CR (or getting too deep into spiritual practices and so on).

My own experience gives me also additional more subtle signs that I can not interpret as good - higher brain activity during sleep not only cuts the total time and breaks a chunk of sleep into parts but sometimes generates "looped songs running through the sleep time", occasional "semisleep state" - that is definitely shouldn't happen. Not only excercises like keeping balance on promoted by Attia blackboard becomes harder but also it is more tricky to keep the line moving fast on narrow curved trajectory (especially on pavements with different colors and lines forming the mosaic of bricks) - brain seems simply lacks energy to efficiently crunch visual signals (Hubermann talked about this somewhere). And there are more similar signs of performing worse than own standard (not talking about peak performance, that is a different story) when brain is too limited in calories (slower talking for example).


I think having 0 of 5 defined criteria is in any case a good indicator that personal lifestyle strategy is correct, before 65 or something like this. And could be a sign of something worse coming after this mark, maybe still modifiable.

Also this angle of view is more or less free from marketing that novadays creates strange chymeras that requires tonns of time to be spent just to understand that it worse nothing, at least - not convertible into own outcomes (even better if measurable).



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Wider criteria set for frailty from "Outcome instruments to measure frailty: A systematic review"




Nutritional status
- Body weight
- Appetite
- Body Mass Index (BMI)

Physical activity
- Level of physical activity
- Leisure time physical (group) activity

- Difficulty or needing help walking/moving in and around the house
- Gait speed

- Tiredness
- Energy level (for example exhaustion/fatigue)

- Lifting an object that weighs over 5 kg
- Weakness in arms and/or legs
- Performing chair stands
- Climbing stairs
- Grip strength
- Calf muscle circumference

- Memory problems
- Diagnosed dementia or cognitive impairment

- Depression/depressed mood
- Sadness
- Anxiety
- Nervousness

Social relations/social support
- Social recourses (when help is needed, can someone provide this?)
- Emptiness/missing people around


There is almost a page of references what could be included to define a condition, but nevertheless, a framework based on keeping an eye on all these things could be a working tool. Useful books (like Fontana's one) seems propose the similar approaches and list of indicators.



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A potential overlap of frailty and inflammation evaluated and despite it seems authors "begged the data" for confirmation (at least it looks for me like that, maybe i am wrong in it):

"Inflammation and frailty in the elderly: A systematic review and meta-analysis"




In conclusion, frailty and pre-frailty are associated with higher inflammatory parameters levels, in particular CRP and IL-6. However, longitudinal studies did not confirm these findings, suggesting that other studies are needed to better understand if these inflammatory markers could be used as potential biomarkers of frailty in the elderly.


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