I'm troubled by something. Longevity Quotient and mTOR per cell, Please poke holes

I might have found a hole in the theory that mouse results are translatable to humans.

Specifically, I just came upon the concept of Longevity Quotient (LQ). That is, in mammalian species, longevity increases with body mass, and you can calculate expected life span based on body mass.

LQ measures how much a specie’s actual lifespan exceeds its expected lifespan based on body mass. For instance, a human has an LQ = 4-5, so we live 4x-5x longer than expected. A mouse’s LQ = 0.7, so it lives 70% as long as expected.

This is all established science.

So why does this matter?

Well, I did some additional research (admittedly not much), and one explanation for the relationship between body mass and lifespan might be that mTOR per cell decreases as body mass increases (as does basal metabolic rates, and other factors relevant to longevity). Thus, higher body mass = lower mTOR per cell = longer lifespan.

And then I did some more research (again not much), and one explanation for why some species (e.g. humans) have a higher LQ than others (e.g. mice) is that its actual mTOR per cell based on body mass is lower than its expected mTOR per cell based on body mass.

So that creates the following problem. If mice have an LQ of 0.7, indicating a higher than expected mTOR per cell and a lower LQ. And if humans have an LQ of 4-5, indicating a lower than expected mTOR per cell and higher LQ. Then might might that indicate that lowering a mouse’s relatively high mTOR would increase its LQ more than lowering a human’s relatively low mTOR.

Please poke holes.

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The first hole is the naked mole rat. Tiny creatures that can live upwards of 40 years.

Joe the mole rat was 39 two years ago. Can’t find an update after that. Even 39 is brilliant. No one really knows how old they can truly get as these are the first batches raised in captivity. Considering he’s virile and active at 39, I’m guessing he may go into his 50s-60s.

The secret lives of naked-mole rats :: Understanding Animal Research.

Naked mole-rats can live longer than any other rodent, with lifespans in excess of 37 years; the next longest-lived rodent is the African porcupine at 28 years.[38][39] The mortality rate of the species does not increase with age, and thus does not conform to that of most mammals (as frequently defined by the Gompertz-Makeham law of mortality).[39] Naked mole-rats are highly resistant to cancer[40] and maintain healthy vascular function longer in their lifespan than shorter-living rats.[41] Queens age more slowly than other naked mole rats.[42]

Then there’s the biologically immortal jellyfish.

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Not really a hole though, because there are no rapamycin studies on mole rats.

So it’s the same problem. The mole rat does have a high LQ like humans. But also like humans, we don’t know if the results for the low LQ lab rat translates to high LQ mole rats and humans.

At least to my knowledge, there is no evidence to support this last part of your argument. Perhaps the relationship between mTOR activity and longevity is linear within the ranges that exist in various mammals.

Also, what is the evidence that LQ is based on mTOR activity/cell? Is this speculation or something supported by measurements across many species?

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Rapamycin seems to be working just as well in monkeys as in mice, given the new data from Adam Salmon. So that would seem to disprove this theory (I’m not sure what the LQ is for these monkeys they used in the UT studies).

See Here: Breaking: 15% Healthy Lifespan improvement via Rapamycin seen in Marmosets

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The Marmoset has an LQ of 1.57, so lower than a human, but higher than a lab rat (0.7).

The study you referenced showed a 15% lifespan increase in marmosets, which is less than for lab rats 23-26% via ITP.

So in a way that supports my speculation that higher percentage lifespan increases in a species could be correlated with lower LQ’s.

You’re comparing apples and oranges here. You need to compare equivalent dosing. Adam Salmon told me that that 1mg/kg dosing they are doing on the marmosets is equivalent to the 14ppm dosing in the mice, and in both mammals they get around 14% lifespan improvement (at least in males, the female mice have a surprisingly high level of blood sirolimus from the studies).

Sirolimus
Dose
Mouse
mg/kg/day
Dose
Mouse:
Blood/Sirolimus
Level
Human
mg/kg/day
Dose
Dose for 60kg Human Daily Dose adjusted for longer half-life (/4)
4.7ppm ∼2.24 3 to 4 ng/mL 0.182 mg/kg 10.92 mg 2.73 mg
14ppm ~6.67 9-16 ng/mL 0.542 mg/kg 32.54 mg 8.135 mg
42ppm ~20 23-80 ng/mL 1.626 mg/kg 97.56 mg 24.39 mg
126ppm ~60 4.878 mg/kg 292.68 mg 73.17 mg
378ppm ~180 45 to 1800 ng/mL 14.634 mg/kg 878.04 mg 218 mg
Sirolimus
Dose
mg/kg/day
Dose
Blood/Sirolimus
Level
Male Median LS Increase Female Median LS Increase
4.7ppm ∼2.24 3 to 4 ng/mL 3% 16%
14ppm ~6.67 9-16 ng/mL 13% 21%
42ppm ~20 23-80 ng/mL 23% 26%

Based on the FDA animal to human dosing conversion guide here.

Note: ½ life for sirolimus in mice is approx. 15 hours, vs. approx. 62 hours in humans. So, mice metabolize sirolimus approximately 4 times faster than humans.

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So I am definitely speculating about whether the lifespan increase from rapamycin might be inversely correlated with a specie’s LQ.

That is, high LQ = low mTOR activity relative to body mass = less percentage lifespan extension from rapamycin intervention.

That speculation is based on certain facts that I think are indicated (but probably not established). To wit, that species with a high LQ have low mTOR activity relative to their body mass.

Can you provide any references that you found compelling on this point?

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How then to explain why Great Dane, 170 lbs, lives on average 7 years and a chihuahua, 3-4 lbs lives up to 20 years? Mine who died in Jan was 19.5 years old.

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The concept that longevity generally increases with body mass in mammals is widely accepted in the field of comparative biology, but it is to be applied between species, not within species.

Full disclosure: I do most of my scientific research using Consensus, which is an AI built on ChatGPT that uses a database of 200 million academic papers.

I’ll go over my prior research and do some more as well and get back to you. To give you my current understanding: there is an established formula for expected life span per species based on body mass, and thus, we can measure the deviation for what is expected (LQ). But there is not an established formula for determining the expected mTOR activity per species based on body mass or whatever the relevant physiological parameter would be, and thus, no way to measure the deviation from what is expected. So I can’t say definitively that human mTOR activity is relatively low or lab rat mTOR activity is relatively high. But my research indicated it was a reasonable supposition. I’ll spell that out in a later post.

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Interesting new tool - thanks for sharing:

People talking about their favorite AI tools:

https://www.reddit.com/r/GradSchool/comments/125ho7u/whats_your_favourite_new_ai_tool_mine_is_consensus/

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