Hallmark of Aging 6 Deregulated Nutrient Sensing

June 15, 2024

Hallmark of Aging 6 Deregulated Nutrient-Sensing

This is one of the most preserved genes in all living cells. There is a choice! Lots of nutrients and you can grow, blossom, reproduce and die, or you can have less nutrients and hunker down and live longer. Can't have both. You choose.

Valter Longo described this in single cell yeast and in fruit flies, earthworms, mice and humans. All the way up the evolutionary ladder. Nutrient sensing is key to the balancing of that teeter-totter.


The mechanistic target of rapamycin (MTOR) complex-1 (MTORC1) responds to nutrients, including glucose and amino acids to modulate the activity of numerous proteins including transcription factors. The MTOR network is a central regulator of cellular activity, including autophagy, mRNA and ribosome biogenesis, protein synthesis, glucose, nucleotide and lipid metabolism, mitochondrial biogenesis, and proteasomal activity. Sensing nutrients is key to all those processes, and mTOR is its means of control.

Diverse hormones like insulin, IGF-1 all play a role in the network feeding back into mTOR. When nutrients are abundant, mTOR turns on "building up and reproducing successfully" and when nutrients are absent or restricted, the reverse occurs: hunker down and slow down metabolism so that you live longer, hoping to outlast the famine. (Every dieter knows this. A prior diet of 800 calories a day fails when one returns to just 1400 calories because their body has gotten lean and mean and turned on nutrient conservation, living longer).

Again, a fascinating rabbit hole if you want to learn what PI3K-AKT and the Ras-MEK-ERK pathways are, or what FOXO3 transcription factors do. But it all comes back to that nuanced teeter-totter of nutrient sensing that falls apart and becomes dysfunctional when we get past 40. Then, we start getting older, and fatter.

Fasting and dietary restriction inhibit MTORC1 and EP300; activate AMPK, SIRT1, and SIRT3. There you have it all in one sentence, non of which you understood. It's complex but again, there are discrete pods of researchers delving into it.. This is, in fact, what Longo advocates for, 5 days of 800 calories at least 4 times a year, better if more often. And the peptide advocates are using rapamycin analogs like Sirulimus that can be prescribed. Longo's fast mimicking diet has been proven to double the effectiveness of chemo therapy and to add 15 years to health span for those who practice it regularly. It induces ketosis.

www.What will Work for me. Ketosis is the sign that you are in nutrient shortage and are beginning to turn on internal autophagy (recycling old pieces to turn into energy) and activating anti-aging mechanisms. There is now some evidence that taking ketones as a daily supplement provides the same benefit. This is a fun little body hack. You can buy ketone esters and ketone drinks now and get into ketosis by just popping the top of a can. The very flavorful new product called Kenetik (www.drinkkenetik.com) dose just that, and every lecturer and teacher of longevity strategies seems to have a bottle of Kinetic at their podium as they speak. At $ 5 a can, it's a bit pricey, but no worse than a Starbucks stop, and likely better for you. I've ordered a six-pack, and son of a gun, it gives a nice boost. Different than coffee.

References: Cell, Science, Ketones, The Fourth Fuel,

Pop Quiz

1. Why is nutrient sensing so important?                              Answer: Organisms have to reproduce and good nutrition helps that happen, but organisms also have to be ready to survive famine. It's a yin and a yang. Live longer, hungry?

2. What are ketones?                               Answer: They are the 4 carbon pieces chopped off of fat molecules that are typically 16 carbons long. So you get four of them out of one fat molecule.

3. How long does it take you to start being in ketosis (making ketones)?                                  Answer: You can only store 1500 calories of carbs. Hence, 12 hours of not eating and you start flipping from running on glucose to running on fat and your blood ketone level will be 0.1. If you do Longo's diet for 5 days (800 calories a day, vegan, <8% protein), by day 5 your ketone level will build each day and be at 3.5-4.0 by day 5. That's full ketosis.

4. How can you use fasting to your benefit?                                   Answer: Longo has demonstrated that done at least 4 times a year results in 15 years of extra health span. This is the most powerful modality we know for anti-aging. You are toggling your nutrient sensing system back into function. But a little less severe will work to. Skip breakfast and concentrate your calories into 8 hours. You get 4 hours of daily ketosis.

5. Is there a book I can read about Ketones.?                               Answer:YES! Ketones, the Fourth Fuel by Travis Christofferson.