mTOR Signaling, Autophagy, and Longevity

Attia: mTOR signaling requires balance — too little causes muscle wasting, too much accelerates aging

Peter Attia

“mTOR forms two distinct complexes (mTORC1 and mTORC2) that operate differently across tissues, and its activity must be carefully balanced. Insufficient mTORC1 activity in muscle leads to wasting and is implicated in muscular dystrophy, while chronic overactivation of the pathway promotes aging and age- related diseases like cancer. This tissue-specific duality means that systemic mTOR modulation strategies must account for context rather than applying a blanket inhibition approach.”

Campisi: fasting may reduce chemotherapy side effects by dampening mTOR activity and clearing senescent cells

Judith Campisi

“Genotoxic chemotherapy induces cellular senescence, and eliminating those senescent cells reduces chemotherapy side effects in mouse models. Short-term fasting may confer similar benefits either by clearing senescent cells or, more likely, by suppressing mTOR activity. mTOR is a highly conserved nutrient- and growth-factor-sensing kinase, and reducing its activity—whether genetically or pharmacologically via rapamycin—extends lifespan across yeast, worms, flies, and mice.”

Attia: on the challenge of measuring mTOR activity in blood as a longevity biomarker

Peter Attia

“A major gap in longevity research is the inability to measure mTOR activity non-invasively in blood, which limits our ability to assess how dietary and lifestyle interventions affect this key aging pathway. Similarly, other growth-promoting pathways like RAS cannot be monitored without invasive tissue biopsies, forcing researchers to rely on indirect proxy biomarkers. Bridging animal studies and human data requires careful judgment in the absence of these direct mechanistic readouts.”

Kroemer: nutrient deprivation and mTOR inhibition as conserved triggers of autophagy

Guido Kroemer

“Nutrient deprivation — whether from absence of food, growth factors, or oxygen — is the most phylogenetically conserved trigger of autophagy, driving cells to catabolize proteins, lipids, and RNA for energy. Three major signaling pathways converge on this response: declining ATP activates AMPK, amino acid scarcity inhibits mTOR, and a third pathway involving cytosolic Acetyl-CoA levels regulates protein acetylation status. Together these mechanisms link cellular energy and nutrient sensing directly to autophagy induction.”

Kroemer: acetylation status connects to mTOR and AMPK regulation of autophagy

Guido Kroemer

“Changes in protein acetylation status indirectly inhibit mTOR and activate AMPK, converging multiple signaling pathways to stimulate autophagy. These pathways are interconnected rather than exclusive, meaning deacetylation reactions simultaneously engage several autophagy-inducing mechanisms. Selective nutrient withdrawal — such as limiting protein intake — may induce autophagy even under normal caloric conditions, potentially through downstream endocrine factors like IGF-1 that feed into mTOR signaling.”

Dr. Guido Kroemer on Autophagy, Caloric Restriction Mimetics, Fasting & Protein Acetylation

Rhonda Patrick

“…u don't have enough amino acids, that can basically inhibit mTOR. And then there's a third one, the protein assimilation pathway, which I'm not as familiar with essentially how that activates autophagy. So, it's actually extremely easy. When you think about ba”

Dr. Guido Kroemer on Autophagy, Caloric Restriction Mimetics, Fasting & Protein Acetylation

Rhonda Patrick

“…before. And similarly, when you give chemical inhibitors of mTOR like rapamycin or the rapalogs, there's also no protein deacetylation. So, you can induce autophagy without protein deacetylation which means that the proxy would be imperfect. So we do have a sy”

Dr. Eric Verdin on Ketogenic Diet Longevity, Beta-Hydroxybutyrate, HDAC Inhibitors & NAD+

Rhonda Patrick

“…ppears to have not only a role as a nutrient, but also as a signaling molecule. Acetyl-CoA is in the Krebs cycle. It’s one of the key intermediary product of the Krebs cycle, but it’s also the substrate for a whole family of enzymes called the acetyltransferas”

Valter Longo, Ph.D. on Fasting-Mimicking Diet & Fasting for Longevity, Cancer & Multiple Sclerosis

Rhonda Patrick

“…etic in the sense where it activates AMP kinase, one of the signaling pathways that also activates.... Do you know if metformin increases autophagy, or has that been looked at? [Valter]: I'm pretty sure it does, yeah, I'm pretty sure it does. So, metformin, in”

Peter Attia, M.D. on Macronutrient Thresholds for Longevity and Performance, Cancer and More

Rhonda Patrick

“…ven, do have a positive effect on the immune system via the signaling molecules that are being made in the gut. So that's very interesting, and it is one thing that I consider when I'm thinking about the effects of diet on longevity. You know, I've focused on”

Valter Longo, Ph.D. on Fasting-Mimicking Diet & Fasting for Longevity, Cancer & Multiple Sclerosis

Rhonda Patrick

“…ents in biology was doing, you know, manipulating the IGF-1 signaling pathway in worms, in Andrew Dillin's lab at the Salk Institute. And I remember when I saw, you know, when you get rid of that pathway in these worms, they live 100% longer. I mean, it was li”

The Science of Protein and Its Role in Longevity, Cancer, Aging, and Building Muscle

Rhonda Patrick

“…s or controversies in the Aging field surrounding igf-1 and mtor Lucine is at the heart of it Lucine is the critical signal driving robust activation of mtor animal protein has a lot of lucing and whether you consider that a good thing or not actually depends”

Dr. Eric Verdin on Ketogenic Diet Longevity, Beta-Hydroxybutyrate, HDAC Inhibitors & NAD+

Rhonda Patrick

“…eally regulate that, and that also regulates aging process, mTOR as well. But, something else that really seems to change with fasting is the NAD levels, and that’s something that, you know, your lab has studied extensively with the sirtuins. So, maybe could y”