What has extended lifespan the most in mice?

What is missing:

I think the highest are, Ross (1961) who got 71% increase on 68% CR and Fernandes et al 1976 got 81.7% increase in males and 70.1% in females on 50% CR. There are many studies reporting between 40 and 50% increase.

https://twitter.com/johnspeakman4/status/1732640477038686279?s=46&t=zJMJ1xVdRJYEDYz-DHipTw

And

Original thread below

  1. VEGF Overexpression (43.8% life extension)
    The Wolverine Hormone.

  2. Telomerase gene therapy (41.4%)
    Extends your telomeres.

  3. FGF21 overexpression (35.9%)
    Previously known as the “Starvation Hormone” - may now be the “sugar” hormone or the “protein restriction” hormone.

  4. Circadian aligned calorie restriction (35%)
    Kinda like intermittent fasting.

  5. Isoleucine restriction (33%)
    Protein restriction, while eating protein.

  6. Follistatin gene therapy (32.5%)
    Become “double-muscle.”

  7. Polypeptide Pineal extract (31%)
    Epithalamin/Epitalon.

  8. Polypeptide Bovine Thymus extract (28%)
    Thymulin/Thymosin/Thymosin Beta-4.

  9. Rapamycin (26%)
    Mimics protein restriction.

  10. N-acetyl-L-cysteine (24%)
    Potent antioxidant, protects liver, neurons.

  1. science.org/doi/full/10.11…
  2. pnas.org/doi/abs/10.107…
  3. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice | eLife
  4. science.org/doi/full/10.11…
  5. cell.com/cell-metabolis…
  6. pnas.org/doi/abs/10.107…
  7. doi.org/10.1016/0047-6…
  8. doi.org/10.1016/0047-6…
  9. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction - PubMed
  10. Life extension by diet restriction and N-acetyl-L-cysteine in genetically heterogeneous mice - PubMed

I’m definitely missing some – link your favorites.

https://twitter.com/ichorgrad/status/1732589374179574092?s=46&t=zJMJ1xVdRJYEDYz-DHipTw

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Why CR works so well on mice?

I think you need to apply the 900 day rule and take out the studies where the control and treated lived less than 900 days.

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The 900 day rule is more a proposal that only the longest lived strains of mice be used so that a median control lifespan of 900 days can be realized. For example, the authors say that metformin doesn’t work in the longest lived strain, but works in other mice strains, so they consider this as evidence that metformin isn’t a true antiaging drug, but rather one that helps to normalize lifespan. This is their theory, and it isn’t proven. It’s a potential explanation for discrepancies between negative ITP results and earlier positive lifespan results from other researchers who may have used more ordinary mouse strains with median lifespans below 900 days.

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Everything you said is correct. I’d still apply the 900 day rule.

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I have always had a different view on CR.
My take is not that CR “extends” LS as “normalises” LS.
In other words, I regard ad lib feeding as the abnormal situation that results in shortened LS.
Few animals eat ad lib in nature.

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Longest lived mice ever were from combination of GH KO (growth hormone knockout) and CR
Second longest lived mice were from GH KO
Third longest lived mice were from CR
Fourth longest lived mice were from Rapamycin + Acarbose or FGF-21 overexpression

Also, Telomerase gene therapy and other things probably work - but they don’t come even close to CR

Telomerase gene therapy had 41% lifespan extension - but it was partly because control was short lived (and obese)

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Interesting how the Top 1, 2 and 3 on your list probably all lowered IGF-1 and total and free T.

Considering how it’s too late to knockout our genes, it seems Rapamycin plus acarbose or metformin is the way to go.

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Perhaps not:

At a near term level they are doing a trial (in NY I think) to move people from Apo E4 to Apo E2 - in old patients with AD risk…

… and we just saw successful trial readouts in editing PCSK9i in humans, as well as FDA approval of knowing our genetics responsible for sickle cell

… at a more aggressive level there are people working on growing any parts of your body (eg swap out you kidney, pancreas, liver and/or bone marrow) based on your own, but younger DNA. In those tissues, it would be easy to edit anything genetically from the outset.

(As discussed on the thread where @RapAdmin was reporting back from the Bay Area Longevity week people are even working on whole (brainless) bodies that you could then transplant your brain into or head onto. That would be based on your DNA, and would be easy to genetically edit at the “embryonic” state)

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As much as I would be happy to have these technologies readily available, I think the pace of development is too slow to be too optimistic.

My methodology is to work with what is currently available. Fortunately, that’s much more than our grandparents had to work with but woefully inadequate to what our grandchildren will have available.

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I think we should do both

  • keep a pulse on what is in the pipeline, what underlying technologies are developing so that we can “skate to where then puck will be” or a least have a good view of the range of outcomes me may see in 5, 10, etc years

  • do what we can today, with the tools that are available today

Sometime the first bullet might help us inform decisions we have to make as it pertains to the second bullet.

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Oh, don’t get me wrong. I love to see what’s in the pipeline for longevity. However experience has taught me to curb my enthusiasm.

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Got it. Yeah, we want neither overoptimism or overpessimism.

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