One of the problems in biomedicine is that attractive models are sticky, meaning that ppl still refer to them even though the underlying premises have been discredited. In science lingo attractive models = "truthiness." Sound right but they are wrong. Here's an example. /1
Ppl are highly influenced by the idea that sirtuins are central regulators of longevity. Many problems with this concept. 1st, SIR2 is only required for 1 (not both) models of yeast longevity. 2nd, there is NO FITNESS ADVANTAGE to yeast mother cells with long lifespans. /2
This means that it is not plausible that SIR2 was conserved as a longevity gene. 3rd, the mechanism by which SIR2 extends lifespan in yeast is not conserved in other organisms. 4th, SIR2 overexpression in worms, flies & mice doesn't make animals live longer. /3
Sensible ppl long ago decided that SIRTs are interesting but are NOT THE CENTRAL REGULATORS OF LIFESPAN. Others, some of whom are very gifted story tellers, turned the SIRT story into a nonfalsifiable hypothesis that all SIRTs do all good things all the time. /4
But this isn't true--SIRTs do some + things for some cells some of the time & at other times are dispensable or destructive. In cancer, they can be oncogenes or TSGs. SIRT3-5 do some interesting things in mitochondria but aren't nearly as critical as other mito proteins. /5
SIRTs are not the most important proteins in DNA repair, not the most important proteins in longevity, not the most important proteins in epigenetics, not the most important proteins in mito function, & not the most important mediators of boosting or restoring NAD. /6
Everyone who studies metabolism knows that 4 NAD coenzymes are central to biological electron flow. You can't get more than 3-4 steps away from any metabolic step without needing NAD or NADP-dependent redox. /7
However, simplistic ppl decided that the primary function of NAD must be to drive SIRT function. This is simply not the case. The redox biology of NAD+, NADH, NADP+ and NADPH are much more essential than the sum of all SIRT functions in any tissue you can name. /8
Even among the non-redox enzymes that use NAD+, the SIRTs are arguably the least regulated. PARP gets activated ~100x by DNA damage. cADPR synthetases go from OFF to ON based on signals received. There is no comparable regulation for SIRTs & I say that as the person who... /9
was 1st to identify an authentic sirtuin activating compound (NR) & demonstrate extended longevity #inyeast. We didn't claim that because we could extend yeast lifespan that we could extend human lifespan bc the data weren't there. When SIRT stories crashed & burned, .../10
we were happy that our horses were not hitched to that wagon. The concept that @GSK bought w respect to resveratrol & other so-called STACs was a house of cards. Resveratrol not a STAC & underlying SIRT lore based on overinterpreted, overhyped & nonreproducible experiments. /11
This brings me to today, where ppl are rediscovering NAD biology, which is great. It's so weird though to see NAD-boosting strategies linked to SIRT biology given the 100s of mission critical NAD-dependent processes in every tissue. /10
It is clear that metabolism, resiliency & repair decline in aging. We've shown that the NAD metabolome is under attack in many conditions of metabolic stress--this leads to heart failure, neurodegeneration, hearing loss, nonoptimal postpartum & I am sure a decline in lifespan./11
I prefer to refer to the role of NR in restoring resiliency & repair capacity as opposed to extending lifespan bc I can readily quantify these things in animals & ppl. I am comfortable with the concept of #agebetter & if we can obtain credible longevity data, I'm all for that./12
We know that both NMN & NR depend on the NR kinase pathway to restore the NAD metabolome & that this pathway is upregulated when cells are under metabolic stress. NAD boosting strategies restore resiliency through multiple NAD dependent pathways. /13
While I am grateful to gifted story tellers for reaching ppl with their NMN "rejuvenation" stories, I'm uncomfortable bc the same ppl have been wrong so many times. We've never cost anyone billions in research costs for an attractive-simplistic-incorrect model & never will. /14
Our work on NAD led to a licensed molecule that has been safety tested, GRAS & NDI notified & is the subject of ~30 clinical trials. We publish our data, positive or negative. We don't overpromise. So, while I'm a less gifted story teller than some, I will never push BS... /15
such as the concept that we don't have to age. Life is possible because of energy inputs driving homeostatic forces that oppose entropy but, in the end, entropy wins. By studying repair & resiliency we can improve human health & potentially add to the evidence-basis for NR. /16
But if someone is pushing a model based on experiments that can't be reproduced in other labs, run the other way. The model may be attractive but is, in the end, a fantasy. /end
