Posted on 28 May 2021
In this series of articles, we discuss the nine ‘common denominators’ of the ageing process – the hallmarks of ageing. What exactly they are, how they change during ageing, and how we might be able reverse them in the future? Hopefully, by the end of this series, you will have a wider understanding of what actually makes us age.
Cells throughout our body require a constant supply of nutrients to provide the energy they need to function, yet our nutrient intake is not constant. Cells must therefore be able to store nutrients when they are abundant and access these stores when nutrients are scarce. Furthermore, nutrient levels in our bloodstream need to stay within certain safe ranges. For example, if blood sugar levels become too low (hypoglycaemia), an individual risks impaired thinking, unconsciousness and even coma and death. If blood sugar levels become too high (hyperglycaemia), organs can be damaged, and various key bodily functions can be disturbed, resulting in a coma and potentially death. Cells must therefore be able to sense nutrient levels in order to respond appropriately, absorbing, metabolising, storing and converting nutrients from one form to another, depending on the circumstances. To this end, a wide range of nutrient signalling mechanisms have evolved that allow the body to keep track of the nutrient balances.
Following a carbohydrate-containing meal, beta cells in the pancreas respond to the rise in blood sugar levels by releasing the hormone insulin, which signals to cells to absorb the sugar from our bloodstream. Certain cells, such as nerve cells, have a constant rate of sugar absorption that is not significantly changed by insulin signalling. Other cells, such as muscle, fat and liver, use insulin as their message from the body to take up more sugars circulating in the blood. Most of this sugar is then converted into a molecule called glycogen to be stored. When blood sugar levels become low, insulin levels decline while the release of its antagonistic hormone, glucagon, increases. This signals to cells to reverse the operation described above, converting glycogen back into glucose and releasing it into the bloodstream.
Other mechanisms, which we won’t discuss in detail here, exist to sense dietary fats and proteins and respond with hormone signals that coordinate the response to these nutrients. In addition to these, signals exist that regulate appetite based on body nutrient abundance. For example, during a fasting period the stomach produces the hormone ghrelin which influences neurons in the brain that control appetite. Its antagonistic hormone, leptin, is produced by fat cells and tells the brain to decrease hunger.
For cells, such hormones serve as external nutrient signals, but cells also have ways to measure their own energy levels. Foremost amongst these is through activation of a protein known as AMPK. This protein is activated when cellular energy levels are low, telling the cell to switch on energy production and switch off any non-essential energy consuming processes. Another important internal sensor is the protein mTOR. mTOR is activated when the level of amino acids (the building blocks of proteins) is high, such as after the consumption of protein rich foods like meat and fish. Numerous other signalling pathways, including the insulin system, also converge on mTOR. Based on the combined strength of these signals, mTOR signalling can determine how to regulate the balance between energy-consuming and energy-saving processes. These include cell growth and division (energy-consuming) and breakdown and recycling of damaged components (energy-saving).
As discussed above, a network of nutrient sensing and signalling pathways work to control when cells should grow and when they should conserve energy in response to nutrient availability. These signalling pathways appear to play a central role in the ageing process. Of the hundreds of genes found to influence lifespan in animal models, a large percentage of them are involved in nutrient sensing, and particularly in the insulin system. The two proteins mentioned above, mTOR and AMPK, have both been linked to lifespan in genetic studies and by pharmacological (drug) experiments. Increased mTOR signalling has a wide range of effects on cellular processes that promote other hallmarks of ageing. Reduced activity of mTOR is beneficial, limiting cell growth and encouraging the repair of damaged cell components. Furthermore, reduced signalling by insulin and its associated growth factors is associated with much of the lifespan extension seen in dietary restriction in animal models.
The main overarching nutrient sensing dysfunction that emerges during human ageing is insulin resistance. With age, factors such as oxidative stress, inflammation, disruption of enzymatic activity and accumulation of fatty acids within cells can all contribute to a reduction in insulin sensitivity – that is to say, cells do not react as well to insulin as they should. These changes can be driven by many of the other entries in this hallmarks of ageing series. The consequence is an increased risk of insulin resistance, in which the body progressively loses its ability to regulate blood sugar levels, with the pancreas producing more insulin in an effort to compensate. Insulin resistance is an extensive topic that is discussed in more detail in this article, but in terms of the ageing process, insulin resistance is a driver for almost all major chronic diseases of ageing. For example, it increases inflammation and oxidative damage (implicated in many diseases), promotes glycation (discussed in ‘Loss Of Proteostasis), and alters fat metabolism in the liver, thereby promoting atherosclerosis and fatty liver disease.
Insulin resistance, the primary manifestation of deregulated nutrient sensing in humans, is usually measured by monitoring blood sugar levels in response to consuming a meal containing carbohydrates. Individuals who are insulin resistant will have higher blood sugar levels for longer. More in-depth ways of examining insulin resistance have also been developed. Nuclear magnetic resonance imaging (MRI) has been used to monitor the movement of glucose between the blood and storage within cells.
It is also possible to measure the levels of components of the nutrient sensing pathways (such as mTOR) using a variety of techniques, such as using antibodies to target specific proteins. This is how we know that dietary restriction can inhibit the activity of mTOR, while exercise appears to activate AMPK.
We already possess multiple drugs that are able to alter nutrient sensing. Rapamycin is a drug used to prevent rejection of organ transplants, and works by selectively blocking mTOR. Feeding rapamycin to mice results in a lifespan extension. What makes rapamycin particularly exciting is that it is able to extend the lifespan of mice even when it is given to them during later life, meaning rapamycin might not be a drug that only works on young people. Metformin is another drug that extends lifespan in animals by activating AMPK and promoting insulin sensitivity. The effectiveness of both of these drugs is currently being studied in human clinical trials.
As already touched on, lifestyle interventions (especially dietary restriction) can counteract changes in nutrient sensing observed during ageing. Forms of dietary restriction such as intermittent fasting can dramatically increase the lifespan of C.elegans worms, fruit flies, mice and rats (by around 60 – 80% or even more), and also reduces their risk of developing age-related disease. What’s more, other hallmarks of ageing such as shortened telomeres and mitochondrial dysfunction can be reduced in animals by fasting. It is still uncertain whether fasting can actually slow ageing in humans, but we can say with confidence that fasting can reduce risk factors for age related diseases in humans. These include insulin resistance, oxidative stress, inflammation, mitochondrial dysfunction and high blood pressure. Unfortunately, conclusive evidence for the effects of fasting on other important markers of ageing (like telomere shortening) is currently lacking.
The Hallmarks of Aging: https://dx.doi.org/10.1016%2Fj.cell.2013.05.039
mTOR and Aging: An Old Fashioned Dress: https://dx.doi.org/10.3390%2Fijms20112774
Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans: https://doi.org/10.1038/nature07583
Short-Term, Intermittent Fasting Induces Long-Lasting Gut Health and TOR-Independent Lifespan Extension: https://doi.org/10.1016/j.cub.2018.04.015
Influence of short-term repeated fasting on the longevity of female (NZB x NZW)F1 mice: https://doi.org/10.1016/s0047-6374(00)00109-3
Effects of intermittent feeding upon growth and life span in rats: https://doi.org/10.1159/000212538
Downregulation of mTOR Signaling Increases Stem Cell Population Telomere Length during Starvation of Immortal Planarians: https://doi.org/10.1016/j.stemcr.2019.06.005
Time-controlled fasting prevents aging-like mitochondrial changes induced by persistent dietary fat overload in skeletal muscle: https://dx.doi.org/10.1371%2Fjournal.pone.0195912
Dietary Restriction, Growth Factors and Aging: from yeast to humans: https://dx.doi.org/10.1126%2Fscience.1172539
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