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Michael R

Rapamycin Improves Vaccine Response in the Elderly

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All:

Rapamycin is by far the best-supported drug (or "drug-type" supplement) potential anti-aging therapy, as most or all of you should know; it is thought to work by inhibiting mTOR, thereby inhibiting protein synthesis and boosting autophagy. Its interactions with the mechanisms of CR in mammals are complex but seemingly not very overlapping, as discussed eg here , here, and most cogently in this context here, suggesting the tantalizing possibility that rapamycin might not be a "CR mimetic" as once thought, but engage a different anti-aging pathway that might be additive to or synergistic with CR mimetics or CR itself.
 
The biggest heretofore-identified potential roadblocks to the use of rapamycin or some modified mTOR inhibitor as anti-aging interventions in humans are diabetic-like side-effects and immune suppression seen in patients given rapamycin for existing indications (mostly, exactly to suppress the immune system, as especially after transplantation).
 
Now, a new study reports that rapamycin can actually enhance the immunological response to vaccination in aging humans:
 

... we evaluated whether the mTOR inhibitor RAD001 [Everolimus -- a rapamycin analog ("rapalog")] ameliorated immunosenescence (the decline in immune function during aging) in elderly volunteers, as assessed by their response to influenza vaccination. RAD001 enhanced the response to the influenza vaccine by about 20% at doses that were relatively well tolerated. RAD001 also reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age. These results raise the possibility that mTOR inhibition may have beneficial effects on immunosenescence in the elderly.(1)

 
The most immediate caveat: simply showing the mounting of a better antibody response after short-term use of the drug is not the same thing as actually showing more effective defense against and clearance of the target pathogen after long-term use of the drug to slow the aging process. In (2),

 

We tested how rapa and CR each impacted the immune system in adult and old mice.

 

We report that each intervention differentially altered T-cell development in the thymus, peripheral T-cell maintenance, T-cell function and host survival after West Nile virus infection, inducing distinct but deleterious consequences to the aging immune system.

 

The latter study has been discussed in this thread on the CR Society Listserv; I should have, but haven't yet, responded to some of Tom's objections to the latter.

 

References
1. Joan B. Mannick, Giuseppe Del Giudice, Maria Lattanzi, Nicholas M. Valiante, Jens Praestgaard, Baisong Huang, Michael A. Lonetto, Holden T. Maecker, John Kovarik, Simon Carson, David J. Glass, and Lloyd B. Klickstein
mTOR inhibition improves immune function in the elderly   
Sci Transl Med 24 December 2014:
Vol. 6, Issue 268, p. 268ra179
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3009892
[No PMID yet]

 

2. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms.
Goldberg EL, Romero-Aleshire MJ, Renkema KR, Ventevogel MS, Chew WM, Uhrlaub
JL, Smithey MJ, Limesand KH, Sempowski GD, Brooks HL, Nikolich-Žugich J.
Aging Cell. 2014 Nov 26. doi: 10.1111/acel.12280. [Epub ahead of print]
PMID:25424641[PubMed - as supplied by publisher] Free Article

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Hi Michael,

 

Have you started taking rapamycin, or thought of starting soon? If so, what dosage would you suggest?

 

Like you and others, I too feel at this stage that rapa (and to a lesser extent, metformin) has potential, but am unsure about the dosage.

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Guest mike

Metformin would mimic CR more closely bAsed on its physiological impact on the human body.

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Hi Michael,

 

Have you started taking rapamycin, or thought of starting soon? If so, what dosage would you suggest?

 

Like you and others, I too feel at this stage that rapa (and to a lesser extent, metformin) has potential, but am unsure about the dosage.

 

I have absolutely not started rapa, and think it would be insane to start it anytime soon. This is an immunosuppressive drug (despite this fascinating short-term antibody response study) that induces diabetes in a significant number of recipients; it's been strongly proven in rodents, but yields relatively small benefits in males and the tested doses closely resemble the doses used in clinical practice for transplant patients. A lot more research is needed before any sensible person would even consider taking this drug for any but the indicated purposes — like the dog study that Matt Kaeberlein and others are trying to organize, and longer-term work in nonhuman primates (see my post "Longish-Term Rapamycin in Primates Seems Safe at Meaningful Doses", 2014/8/10, in the CR Society Listserv once the Archives are back up).

 

Metformin would mimic CR more closely bAsed on its physiological impact on the human body.

 

Never base any decisions based on extrapolations from something's "physiological impact on the human body" ;) . In fact, it is really clear that metformin not at all a CR mimetic. Metformin doesn't extend LS in mammalian models: neither in rats as tested by the NIA, nor in mice as tested by both the NIA's Interventions Testing Program nor by the intrepid Steven Spindler. There was no effect at all in rats; in mice there was a 5% increase in median LS, and none on max.

 

That doesn't mean that there is zero potential role for metformin or analogs thereof as a future longevity drugs: see the intriguing suggestions of an interaction with rapamycin, which really does show (early) promise: the Archives are down just now, but see my post "Re: [CR] Rapamycin & Metformin combo - closer emulation of CR? Newfindings." of 2014/5/21.

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