Hallmark 6 of 12

Deregulated nutrient sensing

Every cell must know whether abundance or scarcity currently prevails and adjust its behaviour accordingly. Four signalling systems handle this: the insulin and IGF-1 pathway, the mTOR complex, AMPK and the sirtuins. Of all twelve hallmarks this is the one with the most intervention data, because intervention is genuinely possible here. It is also the field where the most is overpromised.

Scientific term: Deregulated nutrient sensing
Group: Antagonistic responses
Hallmarks of Aging: Described in 2013

The hallmarks of aging are a research framework, not a diagnostic tool. They describe processes that occur during ageing, but they do not prove causation and are not a basis for medical decisions.

What lies behind it

The insulin and IGF-1 pathway signals nutritional abundance. Insulin controls glucose uptake, IGF-1 mediates a large part of growth hormone action. Both signals switch the cell to growth and storage. Under persistently high intake, receptor sensitivity blunts and insulin resistance develops.

mTORC1 is the central growth switch. Active under nutrient abundance, particularly with plentiful amino acids, it drives protein synthesis and cell growth while simultaneously braking autophagy. Sustained high mTOR activity counts among the best-documented accelerators of ageing in model organisms.

AMPK works in the opposite direction. When the ratio of AMP to ATP rises, meaning energy is short, AMPK becomes active, throttles anabolic processes and switches on degradation and autophagy. The sirtuins, a family of NAD-dependent enzymes, likewise respond to energy status and influence gene regulation via histones among other things.

The disturbance in ageing is not that these systems fail but that they remain stuck in the abundance setting. Growth signals stay active while repair and recycling programmes get their turn less often.

How robust is the evidence

Robust evidence

Consistent human data and mechanistic animal models point in the same direction.

Caloric restriction extends lifespan in yeast, worms, flies and rodents more reliably than any other non-genetic intervention. In primates the outcome was more nuanced: two large rhesus monkey studies reached different conclusions about lifespan but largely agreed that metabolic health and disease burden improved.

For humans, CALERIE provides the most robust data. In this randomised trial, healthy non-obese adults reduced their caloric intake over two years. On average they achieved less than the intended target, yet several cardiometabolic risk markers improved. In a follow-up analysis the pace of ageing measured with DunedinPACE was slower in the intervention group.

Genetically the link is visible in humans too. People with Laron syndrome, in whom the growth hormone receptor is defective and IGF-1 correspondingly low, develop diabetes and cancer strikingly rarely. Their lifespan is not consistently extended, because other causes predominate.

Pharmacologically, rapamycin, an mTOR inhibitor, is the best-documented life-extending substance in mice, even when treatment begins in older age. For humans there are no long-term trials with clinical endpoints. For metformin, which influences AMPK among other things, such studies are under way; robust results in non-diabetics are not available.

Findings in humans

In the randomised CALERIE trial, several cardiometabolic risk markers improved after two years of caloric restriction.
A CALERIE follow-up analysis showed a slower pace of ageing as measured by DunedinPACE.
People with Laron syndrome and persistently low IGF-1 develop diabetes and cancer strikingly rarely.
Insulin resistance and elevated HbA1c are established risk factors for cardiovascular disease and dementia.
Rapamycin extends lifespan in mice even when treatment starts late; human data with clinical endpoints are lacking.

What of this is measurable at YEARS

Partly, via adjacent markers

Alongside epigenetics, this is the hallmark where routine diagnostics come closest to the mechanism. The signalling pathways themselves cannot be measured, but their effects on metabolism certainly can, using established and well-interpretable values.

Fasting insulin and fasting glucose

Insulin sensitivity can be estimated from both. An elevated fasting insulin with still normal glucose is frequently the earliest abnormal finding, often years before long-term blood sugar rises.

HbA1c

Reflects average blood sugar over the past two to three months. An established risk marker with clear thresholds, but slower-moving than insulin and therefore less suited to early detection.

IGF-1

This value reflects the growth hormone axis. Interpretation is delicate, because both very high and very low values are unfavourable and reference ranges are strongly age-dependent. A single value does not serve as a measure of ageing.

Context

These values describe your metabolic state, not your pace of ageing. Neither a protein intake recommendation nor a medication decision can be derived from a single IGF-1 value. Rapamycin and metformin for slowing ageing in healthy people are not approved and, outside of trials, are not supported by endpoint data.

Limits of this hallmark

Transferability of caloric restriction to humans is limited. In short-lived rodents with high metabolic rates it works strongly, in primates considerably more weakly and inconsistently. In humans there is no demonstration that caloric restriction extends lifespan. What is documented are improvements in risk markers over two years.

There are also risks that often get lost in the longevity discussion. Persistently low protein intake and low IGF-1 promote muscle loss in older age and increase the risk of falls and fractures. What can be favourable in midlife is not necessarily so beyond around sixty-five. The evidence argues for age-dependent adjustment rather than permanent restriction.

Caution is warranted with the sirtuins. Some early findings on lifespan extension through sirtuin activation could not be confirmed in independent replications, and the role of resveratrol is now considered considerably weaker than in the original publications. Supplements with NAD precursors are the subject of ongoing trials; a demonstration of benefit for healthy people is so far lacking.

Frequently asked questions

What does deregulated nutrient sensing mean?→

This refers to four signalling systems by which cells recognise whether nutrient abundance or scarcity currently prevails: the insulin and IGF-1 pathway, the growth switch mTOR, the energy-sensing kinase AMPK and the sirtuins. Under abundance the cell switches to growth and storage, under scarcity to repair and recycling. The disturbance in ageing is not a failure of these systems but that they remain stuck in the abundance setting. Growth signals stay active while clean-up programmes such as autophagy fire less often. This state is closely linked to insulin resistance and visceral fat.

Does caloric restriction extend human life?→

This has not been demonstrated, and it will hardly be demonstrable at reasonable cost. Intermediate steps are documented. In the randomised CALERIE trial, healthy adults reduced caloric intake over two years and improved several cardiometabolic risk markers. A follow-up analysis showed a slower pace of ageing measured with an epigenetic clock. Both are measurements, not clinical endpoints. In rhesus monkeys, two large studies reached different conclusions about lifespan while metabolic health improved in both. The cautious summary: caloric restriction improves risk profiles; whether it extends human lifespan is open.

Should you lower IGF-1 to age more slowly?→

That conclusion falls short. It is true that people with Laron syndrome and persistently very low IGF-1 develop diabetes and cancer strikingly rarely. Their lifespan is nevertheless not consistently extended. IGF-1 follows a U-shaped relationship: both very high and very low values go along with unfavourable outcomes, and reference ranges shift strongly with age. In older age a low IGF-1 is linked to muscle loss and frailty. Deliberately lowering it is therefore not a sensible goal, and a single laboratory value justifies neither a dietary overhaul nor a medication.

Where do rapamycin and metformin stand?→

Rapamycin inhibits mTOR and extends lifespan in mice more reliably than any other substance studied, even when treatment starts late. In humans it is approved as an immunosuppressant, not for slowing ageing. Long-term data on benefits and risks in healthy people are lacking, and the known side effects are relevant. Metformin influences AMPK among other targets and is well established in type 2 diabetes. Whether it also benefits non-diabetics is currently under study; robust results are not available. There are also indications that metformin can blunt the training response in muscle. Both substances currently belong in trials, not in self-medication.

Sources

Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493(7432):338–345.
Kraus WE, Bhapkar M, Huffman KM, et al. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. The Lancet Diabetes & Endocrinology. 2019;7(9):673–683.
Waziry R, Ryan CP, Corcoran DL, et al. Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nature Aging. 2023;3:248–257.
Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392–395.
Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Science Translational Medicine. 2011;3(70):70ra13.
Mattison JA, Colman RJ, Beasley TM, et al. Caloric restriction improves health and survival of rhesus monkeys. Nature Communications. 2017;8:14063.

Related hallmarks

Hallmark 5 of 12