Hallmark 6: Dysregulated NutrientSensing
What is Dysregulated Nutrient Sensing?
There are many cues to tell us when we are hungry - it could be the growling and gurgling of the belly, feeling low energy, or even the ring of the lunch bell. On a cellular level, this occurs because our bodies are constantly tracking our food intake and energy needs through built-in systems umbrella termed as nutrient sensing. This helps regulate when we need to store energy, burn fat, grow new cells, or clean up damaged ones.
But as we age, this system can start to misfire. It may respond too strongly to some signals or stop responding altogether - This is known as dysregulated nutrient sensing.
Dysregulated nutrient sensing is one of the antagonistic hallmarks, these differ from the other hallmarks of ageing because at first, they can actually mitigate the effects of the primary hallmarks but, with age, they can become harmful themselves. (1)
The IIS Pathway
One of the most important systems involved is the insulin and IGF-1 signalling pathway (or IIS pathway for short). This pathway is an incredibly conserved process evolutionarily, existing in most organisms from tiny worms to humans (2). It plays a central role in how the body detects and reacts to nutrients, particularly sugar in the blood.
You can think of the IIS pathway like a chain reaction, where one step triggers the next:
A → B → C (see diagram). In a simple example, A influences B, then B influences C. But, B can be acted on by factors outside of the pathway; this means that even if A influences B, B won’t influence C if that outside factor is there (we’ll come to this later).
The simplified IIS pathway:
Growth hormone (A) triggers IGF-1 production (B), which drives a variety of downstream factors (C) influencing ageing. Nutrient restriction can reduce IGF-1 signalling, shifting the body from growth mode into repair mode.
A → B: Growth Hormone -> IGF-1
It may be helpful here to imagine your body as a factory, where the IIS pathway is its central control system - deciding when to increase production, when to scale back, and when it’s time for maintenance. At the top is growth hormone (A) (3), the factory manager, who gives the green light for production. This triggers the release of IGF-1 and insulin, the workers on the ground who ramp up activity, telling your cells to grow, divide, and store energy. When you eat - especially meals rich in sugar or protein - these workers get louder, keeping the factory in “go-go-go” mode. When we’re young, this system easily toggles between building and repair but, with age, the signals can get stuck in “growth mode,” pushing cells to keep dividing even when they should be focusing on recovery. This imbalance can gradually wear the body down from the inside out, what we recognise as cellular ageing.
C → Ageing
Now to explain what we’ve called the ‘variety of factors’ at point C above. The IIS pathway primarily responds to sugar (glucose), but it’s tightly connected to three other downstream nutrient-sensing systems: mTOR, which detects protein levels, and AMPK and sirtuins, which respond to low energy availability. Think of mTOR as the people overseeing building and repair jobs - regulating how the body builds and stores materials. While this is a useful mechanism in moderation, too much mTOR activity, especially later in life, has been evidenced to increase the risk of disease (4).
Moving to AMPK and sirtuins, these processes act as internal sensors that detect when the factory is running low on fuel (5). When energy is down, these sensors trigger a shift into conservation and clean-up mode. They help boost autophagy, improve stress resilience, and even switch off mTOR when appropriate. Activating these pathways has therefore been linked to healthier ageing, largely because they encourage the body to focus on repair rather than relentless growth.
Can we Slow Down to Slow Ageing?
Yes! Research suggests that when this pathway is experimentally downregulated, lifespan and healthspan often improve. Interestingly, in normal ageing, both growth hormone and IGF-1 naturally decline, almost as if the body is trying to ease off the accelerator to protect itself (6). But… as always there’s a balance to be struck. Slow things down too much, or for too long, and you may run into other problems. The goal isn’t to shut the factory down, just to give it time to rest and recover.
Nutrient Sensing
This is where nutrient restriction comes into play, as shown in the above graphic, this can limit the influence of IGF-1 (B) and mTOR (C) (7). When the body senses a lack of nutrients, it’s like hitting the pause button on production. IGF-1 signals are dialled down, and the factory shifts into maintenance mode - activating ‘autophagy’. Nutrient restriction is therefore one of the simplest ways to influence this hallmark and your rate of ageing.
Intermittent Fasting: Giving Your Body Time to Repair
One of the most effective and natural strategies for nutrient restriction is intermittent fasting. Unlike conventional diets that focus on what to eat, intermittent fasting centres on when to eat, allowing the body periodic relief from the demands of constant digestion.
Far from a modern trend, fasting has a body of growing scientific support. Notably, the CALERIE trial - a major human study on calorie reduction - demonstrated that a 15 - 25% reduction in calorie intake over two years led to improvements in mood, vitality, libido, metabolic health, and even cognitive function (8). A broader body of research echoes these findings, linking intermittent fasting and modest caloric restriction with extended healthspan (9-11).
Disclaimer:
That said, fasting isn’t one-size-fits-all. For women in particular overdoing fasting, especially when paired with high stress, intense exercise or at certain points during the menstrual cycle, can sometimes have the opposite of the desired effect. That’s why it’s important to approach fasting as a flexible tool, not a rigid rule, again it’s about that all important balance. Start gently, stay flexible, and listen to your body. Consider working with a healthcare professional to find what works best for you.
Lifestyle tips to ‘re-regulate’ your nutrient sensing systems
Implement Gentle Intermittent Fasting
Simple and evidence-backed fasting schedules include:
16:8 method: fast for 16 hours, eat within an 8-hour window.
5:2 method: eat normally five days per week, reduce intake on two.
These routines have been associated with enhanced metabolic flexibility, improved insulin sensitivity, and reductions in markers of inflammation and oxidative stress.
Moderate Protein and Sugar Intake
Diets high in animal protein can overly stimulate mTOR, a growth-promoting pathway. Aim for moderate protein levels and include plant-based sources where possible.
Minimise refined sugars, which trigger sharp insulin spikes; instead, favour whole grains, legumes, fruits, and vegetables for more stable energy and blood sugar control.
Prioritise Physical Activity
Regular exercise, particularly moderate weight training, enhances insulin efficiency, maintains lean muscle mass, and activates key repair pathways. Movement is a vital signal that complements dietary strategies.
Optimise Sleep and Manage Stress
Chronic stress and insufficient sleep elevate cortisol, disrupting glucose regulation and fat metabolism. Practices such as meditation, nature walks, or breathwork, paired with consistent, high-quality sleep, help restore balance in the body's regulatory systems.
Future Directions in Healthcare
Scientists are exploring therapies that target nutrient sensing, including low-dose rapamycin to quiet the mTOR pathway, and metformin to activate AMP-activated protein kinase (AMPK) and promote a repair-focused state.
Compounds like nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and naturally occurring spermidine are also being studied for their ability to boost nicotinamide adenine dinucleotide (NAD⁺) and support sirtuin activity - helping cells function more youthfully and clean up damage (12-14).
(please see the glossary if some of the names in here are unfamiliar.)
Bottom line:
Our bodies rely on a network of signals to decide when to build and when to repair. As we get older, it can become harder for the body to rely on this system so we need to find ways of helping it out. The takeaway is to find a balanced rhythm: give your body regular breaks to rest and repair this system. A slightly slower pace today could mean a healthier, longer life tomorrow.
Glossary
Insulin and IGF-1 - Hormones that regulate blood sugar and promote growth.
IIS Pathway (Insulin/IGF-1 Signalling) - A key nutrient-sensing pathway that influences metabolism, growth, and lifespan.
Growth Hormone (GH) - A hormone that stimulates IGF-1 production, cell growth, and regeneration.
mTOR (mechanistic Target of Rapamycin) - A protein that promotes cell growth and is inhibited to trigger autophagy and extend lifespan.
AMPK (AMP-activated Protein Kinase) - An energy sensor that activates repair processes and inhibits mTOR during low-energy states.
Sirtuins - A family of enzymes that depend on NAD⁺ and help regulate aging, stress response, and metabolism.
Rapamycin - A drug that inhibits mTOR and mimics calorie restriction, studied for anti-aging effects.
Metformin - A diabetes drug that activates AMPK and may promote longevity and metabolic health.
NAD⁺ (Nicotinamide Adenine Dinucleotide) - A coenzyme essential for energy production and DNA repair, declining with age.
Nicotinamide Riboside (NR) - A precursor to NAD⁺ that supports energy metabolism and healthy aging.
Nicotinamide Mononucleotide (NMN) - Another NAD⁺ precursor that may boost cellular repair and mitochondrial function.
Spermidine - A natural compound that promotes autophagy and has been linked to increased lifespan.
References:
López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278. doi: 10.1016/j.cell.2022.11.001. Epub 2023 Jan 3. PMID: 36599349
Mathew R, Pal Bhadra M, Bhadra U. Insulin/insulin-like growth factor-1 signalling (IIS) based regulation of lifespan across species. Biogerontology. 2017 Feb;18(1):35-53. doi: 10.1007/s10522-016-9670-8. Epub 2017 Jan 18. PMID: 28101820
Hage C, Salvatori R. Growth Hormone and Aging. Endocrinol Metab Clin North Am. 2023 Jun;52(2):245-257. doi: 10.1016/j.ecl.2022.10.003
Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017 Mar 9;168(6):960-976. doi: 10.1016/j.cell.2017.02.004. Erratum in: Cell. 2017 Apr 6;169(2):361-371. doi: 10.1016/j.cell.2017.03.035
Burkewitz K, Zhang Y, Mair WB. AMPK at the nexus of energetics and aging. Cell Metab. 2014 Jul 1;20(1):10-25. doi: 10.1016/j.cmet.2014.03.002. Epub 2014 Apr 10. PMID: 24726383; PMCID: PMC4287273
Pataky MW, Young WF, Nair KS. Hormonal and Metabolic Changes of Aging and the Influence of Lifestyle Modifications. Mayo Clin Proc. 2021 Mar;96(3):788-814. doi: 10.1016/j
Wu Z, Isik M, Moroz N, Steinbaugh MJ, Zhang P, Blackwell TK. Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity. Cell Metab. 2019 May 7;29(5):1192-1205.e8. doi: 10.1016/j.cmet.2019.02.013. Epub 2019 Mar 21. Erratum in: Cell Metab. 2021 Oct 5;33(10):2090. doi: 10.1016/j.cmet.2021.08.016
Kraus WE, Bhapkar M, Huffman KM, Pieper CF, Krupa Das S, Redman LM, Villareal DT, Rochon J, Roberts SB, Ravussin E, Holloszy JO, Fontana L; CALERIE Investigators. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol. 2019 Sep;7(9):673-683. doi: 10.1016/S2213-8587(19)30151-2
Dorling JL, Martin CK, Redman LM. Calorie restriction for enhanced longevity: The role of novel dietary strategies in the present obesogenic environment. Ageing Res Rev. 2020 Dec;64:101038. doi: 10.1016/j.arr.2020.101038
Tizazu AM. Fasting and calorie restriction modulate age-associated immunosenescence and inflammaging. Aging Med (Milton). 2024 Aug 12;7(4):499-509. doi: 10.1002/agm2.12342
Martin CK, Bhapkar M, Pittas AG, Pieper CF, Das SK, Williamson DA, Scott T, Redman LM, Stein R, Gilhooly CH, Stewart T, Robinson L, Roberts SB; Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) Phase 2 Study Group. Effect of Calorie Restriction on Mood, Quality of Life, Sleep, and Sexual Function in Healthy Nonobese Adults: The CALERIE 2 Randomized Clinical Trial. JAMA Intern Med. 2016 Jun 1;176(6):743-52. doi: 10.1001/jamainternmed.2016.1189
Roark KM, Iffland PH 2nd. Rapamycin for longevity: the pros, the cons, and future perspectives. Front Aging. 2025 Jun 20;6:1628187. doi: 10.3389/fragi.2025.1628187
Soukas AA, Hao H, Wu L. Metformin as Anti-Aging Therapy: Is It for Everyone? Trends Endocrinol Metab. 2019 Oct;30(10):745-755. doi: 10.1016/j.tem.2019.07.015
Shade C. The Science Behind NMN-A Stable, Reliable NAD+Activator and Anti-Aging Molecule. Integr Med (Encinitas). 2020 Feb;19(1):12-14. PMID: 32549859; PMCID: PMC7238909
Author: Georgia Pilling
