In this study Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice the maximum lifespan of the mice was increased by 17.8%.
... and 10% in males — as I said in my post 
. My point was simply that it's (unintentionally) misleading to say that it increased "lifespan" by 23% (as you'd originally said), when it actually increased median age at death by 23%: the increase in max LS was significantly smaller, particularly in males (which is in line with previous reports).
As Blagosklonny and Dr Green have both explained, intermittent dosing is much preferred for lifespan extension purposes.
That's certainly what they argue, based on the pilot study reported in these two papers (same study, separate paper, looking at different outcomes —as I discussed above (and following posts in my exchange with Smithx); they also reference some questionable evidence using short-lived and/or mutant mice, such as this. This line of evidence does broadly tend to support that argument, but this is only a pilot study, as I explained previously: to say it with any confidence, even in mice, it will need repeated in a larger study (as Dr. Lamming himself acknowledges) and with a more convincingly healthy control group.
Increasing maximum lifespan does not rule out having a long slow decay
Push out the median lifespan enough and you "square the box".-- healthy to the end.
First, to be clear, no one is arguing that it's attractive to have an agent that increases max with no effect on median: that suggests a very stressful and dangerous intervention that happens to also retard aging. However, you also don't want to take too seriously effects on rodent median age at death, and particularly not in this study, for reasons given.
You are, however, not thinking clearly in asserting that if you "Push out the median lifespan enough and you "square the box"-- healthy to the end." Again, increasing median age at death without a concomitant increase in maximum LS indicates you've largely prevented premature deaths, without affecting underlying aging processes. (Heck, people who die very prematurely are often ostensibly pretty "healthy", but only because they are disproportionately vulnerable to some singular pathology and haven't yet suffered with the degenerative aging process (viz. the huge epidemic of seemingly-healthy 40-60-year-olds who were dropping dead of heart disease back from WWII through the early 70s. As we made progress against CVD in the ensuing decades — by lowering saturated and trans-fatty acid intake, lowered smoking rates, introduced blood pressure meds and then statins, and to a small extent interventional cardiology — we prevented a lot of those premature deaths, increasing median age at death — but people who would have died largely "healthy" in middle age instead wound up less healthy when they died decades later. That beats the alternative, but it illustrates the point: reducing premature mortality alone does not leave one "healthy to the end").
Where you really see a shortened period of age-related morbidity is exactly with interventions that actually slow aging, resulting in median and maximum lifespan increasing concert, whether it's CR,(1) or IGF-1 mutations,(2-4) or human centenarians(5) (especially genetic centenarians)— or, yes, rapamycin.
References
1. Shimokawa I, Higami Y, Hubbard GB, McMahan CA, Masoro EJ, Yu BP. Diet and the suitability of the male Fischer 344 rat as a model for aging research. J Gerontol. 1993 Jan;48(1):B27-32. PubMed PMID: 8418135.
"morphologic lesions indicating the cause of death were not found in 25% or more of the rats in Groups B [CR with casein as the protein source] and S [CR with soy as the protein]; such was the case for less than 8% of the rats in Groups A [AL casein] and L [AL lactalbumin]. … Indeed, most striking is the finding that at the time of spontaneous death, 22 of the 79 Groups B and S rats showed an absence of any morphologic lesions likely to play a causal role in the death of the rat, while such was the case in only 5 of the 80 rats in Groups A and L. Moreover, in the rats of Groups B and S, 16 of the 22 deaths without significant morphologic lesions occurred at advanced ages (> 30 months) while in the rats of Groups A and L, three of the five occurred at young ages (< 24 months)." (1)
2: Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke A. Delayed occurrence of fatal neoplastic diseases in ames dwarf mice: correlation to extended longevity. J Gerontol A Biol Sci Med Sci. 2003 Apr;58(4):291-6. PubMed PMID: 12663691.
"Approximately 25% of the dwarf mice died without obvious evidence of lethal pathological changes", vs none of the WT (Table 1)"
3: Vergara M, Smith-Wheelock M, Harper JM, Sigler R, Miller RA. Hormone-treated snell dwarf mice regain fertility but remain long lived and disease resistant. J Gerontol A Biol Sci Med Sci. 2004 Dec;59(12):1244-50. PubMed PMID: 15699523; PubMed Central PMCID: PMC2924623.
47% of Snell dwarves vs 7% of controls dying with no obvious pathological cause -- and notably, "there were no obvious differences in lesion frequency attributable to hormone exposure [in dwarves treated or not with GH and thyroxine to restore these hormones to normal levels for the first 11 weeks of life], although small group size precluded detailed analysis of this issue" -- and notably, albeit of no relevance to late-onset intervention, early developmental hormone treatment "increased their weight by approximately 45%, although they remained much smaller than controls ... [and] restored fertility to male dwarf mice ... [but] did not diminish life span or lower the resistance of dwarf mice to cataracts and kidney disease"
4: Ikeno Y, Hubbard GB, Lee S, Cortez LA, Lew CM, Webb CR, Berryman DE, List EO, Kopchick JJ, Bartke A. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J Gerontol A Biol Sci Med Sci. 2009 May;64(5):522-9. doi: 10.1093/gerona/glp017. Epub 2009 Feb 19. PubMed PMID: 19228785; PubMed Central PMCID: PMC2667132.
"Approximately 58% of GHR/BP KO mice died from nonneoplastic lesions, compared with approximately 17% for the WT littermates, mainly due to the high incidence of death cases in GHR/BP KO mice (approximately 47%) with no obvious evidence of lethal pathological changes."
5: Paul Gellert, PhD Petra von Berenberg, PhD MD MPH Monika Oedekoven Maria Klemt Christine Zwillich Stefan Hörter, PhD Adelheid Kuhlmey, PhD Dagmar Dräger, PhD Centenarians Differ in Their Comorbidity Trends During The 6 Years Before Death Compared to Individuals Who Died in Their 80s or 90s
The Journals of Gerontology: Series A, glx136, Published: 29 June 2017
Edited by Michael, 11 August 2017 - 02:10 AM.
