NAD⁺ — research review 3

...and this is why NAD+, nicotinamide adenine dinucleotide, is such a hot topic. It’s a central coenzyme for energy and sirtuins, and we know its levels decline as we age.

Right, and the longevity thesis is that restoring those NAD+ levels could prevent age-associated metabolic decline and even promote longevity in model organisms. We see in Cell 2013, that NAD+ is a rate-limiting substrate for sirtuin deacylases, and its restoration promotes longevity in worms.

It also activates stress signaling pathways, like the FOXO transcription factor DAF-16, which is pretty fascinating. And we know NAD+ is crucial for sirtuins like SIRT1 and SIRT3, which are key for metabolic health and energy. Without enough NAD+, these longevity enzymes can't do their job effectively.

Exactly. And other things consume NAD+, too. Take CD38, an ecto-enzyme whose activity rises with age. Nature Metabolism 2020 noted that an increase in CD38 in white adipose tissue and the liver during aging decreases NMN and NAD+ levels. Plus, PARP enzymes consume NAD+ during DNA repair, competing with sirtuins for that same pool, as detailed in Molecules 2018.

So, it’s a tight balance. What's still genuinely unknown, though? We have these promising findings in model organisms, but what about human longevity? We see exercise and dietary restriction modulate NAD+ pathways, and certain foods like milk and fish contain NAD+ precursors.

Yes, the big question is how directly these preclinical findings translate to extending healthy human lifespan. While precursors like nicotinamide riboside can raise NAD+ metabolome in older adults, as shown in Cell Reports 2019, proving a direct causal link to human longevity or disease prevention in the long term is still unproven. We need more robust, long-term human data to confirm these effects.