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Scientific Evidence for lifespan interventions on this forum

scientific evidence in-vivo in-vitro lifespan

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#1 Guest

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Posted 19 October 2020 - 02:17 PM

I sometimes wonder, what concept of scientific evidence is acceptable - and if some members of this forum are aware of the differences in standards.


Now let’s be clear: people can have different standards for risk taking depending on their individual circumstances. If you have a specific and severe medical condition or are of quite advanced age you might be willing to try sometimes unproven substances. That is understandable and is not part of my elaboration.


But there should be no dissent on what constitutes good scientific practice and evidence. Therefore sometimes I find it difficult to understand the excitement of some (not all) about a broad array of supplements.


In this thread I want to focus on supplements and interventions that promise an increase in life-span – your rapamycin & Co. Please correct me if I’m wrong, but in order of validity this is the main type evidence you can encounter:



Place number 1. Well done placebo-controlled studies in humans.


The gold standard. Not fool-proof – dosing can be sub-clinical, it can be underpowered etc. – but it’s the best there is. After a couple of years of follow-up there should be markedly reduction in mortality numbers.



2. (longitudinal) Epidemiological studies in humans.


Just behind RCTs. Ideally prospective cohort studies of sufficient time-span and magnitude. If controlled for a lot of relevant confounding factors it can at least give a good indication that there might be an effect.


Problems: can easily be under-powered (ideally you have 100.000s participants) , ridden with statistical artifacts (monitoring and censoring effects in the intervention group etc.), lack of information about dosing/adherence, not accounting for important confounders



3. Lifespan studies in rodents or monkeys.


Mice (and monkeys) are not Men. But evolutionary they are fairly close – compared to c.elegans. If you have an intervention, that prolongs life in mice – or even better monkeys – it’s at least indicative that it might work in other mammals.


Problems: bad animal husbandry can distort the effect of interventions - unusually short lived or metabolically deranged controls are a sign for that. The mice model might be a heavily in-bread or genetically modified disease-model (which makes it hard to understand the relevance for “normal” humans). The study might be just under-powered or lack a control group.




These 3 – in descending order – are what I would consider necessary evidence to at least consider an intervention as a possible strategy. You still have to spend a lot of thought on something, if the only data supporting improved mortality is coming from mice (is the dosing really translatable to humans? Etc.)


The following evidence is more problematic. It can serve as support for data uncovered in 1.-3. or help to explain the mechanisms of action. But in and by itself it is in my eyes not a justification to do an intervention. Or vice-versa it cannot counter-proof positive results from 1.-3. :



4. case-control studies in humans


5. case-studies in humans and anecdotal evidence


6. studies in primitive organisms (flies, c.elegans, yeast cells)


7. ex-vivo and tissue studies


8. in-vitro studies



Especially 8. - in-vitro studies – are often over-interpreted.


Generally their only use in my opinion is for analyzing the mechanisms of action for certain interventions to better understand their application. You might find an interesting bio-marker or intra-cellular process that can help to judge the dosing of a substance found in 1.-3. But it is unsettling that frequently authors are giving a call-for-action entirely based on an in-vitro result (despite a dosing which literally is 1000 times the human dosing and no knowledge of metabolic interactions in living animals). They are easy and cheap to do – so you sometimes find dozends of in-vitro study for every in-vivo study on pubmed. But they are really the weakest evidence you can look for to judge an intervention for its results.




I’d like to hear if you follow this reasoning so far about the quality and validity of scientific evidence.

Edited by Guest, 19 October 2020 - 02:20 PM.

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#2 Guest

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Posted 19 October 2020 - 02:21 PM

In this next post I like to collect the kind of evidence available for certain very popular substances and interventions for lifespan on this forum. Particularly focused on evidence 1., 2. and 3. - please correct me if I’m missing something:





3. lifespan studies in mice

There are actually quite a lot of them, starting at different ages and dosing (older age an lower dose is less effective). Problem: dosing is difficult to translate to humans





2. one epidemiological study in the UK

Problem: monitoring and censoring effects undermine the results


3. lifespan studies in mice

Problem: inconsistent; sometimes works – sometimes doesn’t work; metabolically deranged mice benefit; null-results for normal mice; little to no effect in older mice





3. lifespan study in mice

the one lifespan study done in mice yielded a null-result (a non-statistically significant 26,4 vs. 27 month median lifespan)





3. lifespan studies in mice

2 studies demonstrated life-extension in mice; dosing can be translated to humans





3. lifespan studies in mice

one study demonstrated life-extension; very large effect – therefore strange that it never has been replicated





(1.-2.) limited evidence in cancer patients – which is not your normal consumer

epidemiological data for cancer occurrence (but not all-cause mortality)

epidemiological data for vegetable consumption in general (but not the specific substance)





no evidence for 1.-3.





I'm not doing this exercise to downplay or offend anyone (I myself am taking 2 of the mentioned substances) - but to compare the evidence and understand why some members are so overly cheery about certain interventions.


If you know of any other substance or intervention that is generally assumed to have lifespan benefits please feel free to add to this and what category of evidence is available for it.

Edited by Guest, 19 October 2020 - 02:28 PM.

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#3 Gal220

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Posted 20 October 2020 - 04:21 AM

Difficult to put all the pieces together, but I normally put the most weight on restoring bio markers to younger measured levels like DHEA and testosterone. It doesnt take alot as LEF likes to promote, just a few milligrams of DHEA, 2mgs for every decade after 30. 


It would be nice to find the root cause of course, but you do the best you can.  Senolytics and improving stem cells with c60 just makes sense.


I think there are safer methods of autophagy - caloric restriction than rapamycin and metformin, but I understand why someone would use them.



The experience threads for NR / NMN + Resveratrol on boards like these are also helpful, not sure they are the best way to restore NAD+, but it makes sense to do so.


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