Back in 2014, a group of researchers conducted a study comparing two drugs for type II diabetes: metformin and a sulfonylurea. Sulfonylureas had been linked to an increased risk of cardiovascular events and death compared with metformin, and they wanted to study this in more detail. What they found was rather intriguing: not only did diabetics on metformin live longer on average than those taking sulfonylureas, but they also lived longer than the matched non-diabetic control group.
It has emerged that multiple drugs targeting diabetes mellitus may also modulate the ageing process. Indeed, of the 6 compounds so far shown convincingly to extend lifespan in mice, two are used to treat diabetes, and a third targets pathways closely linked to insulin and glucose metabolism.
What is the link between diabetes, blood sugar, and the ageing process? Insulin is released by the pancreas in response to a rise in blood sugar, and serves as a signal telling cells that energy is available and that now is the time to engage in energetically demanding processes, such as growth and cell division. When blood sugar and insulin are low, this informs cells that energy is scarce, pushing them towards a kind of ‘survival mode’ in which they focus on repairing damage. This damage repair is thought to be central to the link between glucose and ageing, as it counters several processes thought to be instrumental in ageing, such as DNA damage, mitochondrial dysfunction and oxidative stress.
The pathway that controls how cells respond to glucose and other nutrients is called the nutrient sensing pathway, and offers several promising targets for anti-ageing drugs. One such target is mTOR, the target of the drug rapamycin, which is arguably one of the most promising anti-ageing drugs we know of currently. However, the nutrient sensing pathway is not the only mechanism through which blood sugar can affect the ageing process. Glucose itself binds to proteins throughout the body in a process called glycation, resulting in the formation of molecules called advanced glycation end-products. These molecules can form bonds called cross-links between other proteins, resulting in detrimental effects in a variety of tissues throughout the body. These include stiffening and loss of elasticity in the walls of the heart, the blood vessels, and the skin.
Due to these relationships between blood sugar, insulin, and ageing, diabetes drugs are of interest as a potential source of compounds that could modulate the ageing process in healthy people. Almost all drugs for diabetes mellitus aim to lower blood sugar, but the mechanisms by which they achieve this vary. Some operate through insulin signalling, either by stimulating the secretion of insulin itself, or by enhancing the insulin sensitivity of cells (meaning that less insulin is required to achieve a given reduction in blood sugar). Others affect blood sugar in other ways, such as by slowing the digestion of carbohydrates or limiting the reabsorption of glucose by the kidneys. What follows is a collection of currently available diabetes drugs grouped by general class, with a brief summary of their mechanism of action. Could any of these drugs slow ageing in humans?
Examples: Chlorpropamide, Tolazamide, Acetohexamide, Glyburide, Glipizide, Glimepiride
Mechanism of action: Sulfonylureas work mainly by blocking a protein channel expressed by beta cells in the pancreas, resulting in the increased release of insulin. This means they are only effective in patients with functioning beta cells. Certain sulfonylureas also increase sensitivity to insulin in some tissues.
Examples: Repaglinide, Nateglinide.
Mechanism of action: Meglitinides work by stimulating the release of insulin from pancreatic beta cells through a very similar mechanism to sulfonylureas. They target the same protein channel, but bind to it at a different site.
Examples: Metformin, Buformin, Phenformin
Mechanism of action: The only biguanide that is currently available in the United States and many other countries is metformin, a drug that has been of significant interest in the field of ageing research. Research suggests that type II diabetics taking metformin actually live longer on average than age-matched non-diabetics, leading many to postulate that metformin may be beneficial even in healthy individuals. However, the effects of metformin on mouse lifespan have been surprisingly mixed, failing to show significant lifespan extension in ITP trials.
The mechanism of action of metformin is not well understood. It works partly by reducing production of ATP (the cell’s primary fuel source) by the mitochondria. Since the production of glucose in the liver is heavily dependant on ATP, this inhibits glucose production (gluconeogenesis), and also inhibits the breakdown of glycogen (a form of glucose storage). Metformin also has a variety of other effects, including decreasing intestinal glucose absorption, increasing insulin sensitivity, and increasing glucose uptake into cells from the blood.
Examples: Rosiglitazone, Pioglitazone
Mechanism of action: Thiazolidinediones work by activating a group of receptors called PPARs. This causes adipose (fat) tissue to store more fatty acids, decreasing the amount of fatty acids circulating in the blood. This, in turn, means that cells must utilise more glucose to provide the energy necessary for cellular processes, decreasing the amount of glucose in circulation.
Examples: Acarbose, Miglitol
Mechanism of action: These drugs inhibit enzymes called alpha-glucosidases located on the walls of the small intestine. These enzymes break down complex, insoluble carbohydrates into soluble forms that can be absorbed by the gut. Blocking them reduces the absorption of carbohydrates, leading to a reduction in blood sugar.
Acarbose appears to be capable of extending lifespan in mice. One study found that it was able to extend median lifespan by 22% in males and 5% in females when given at 4 months of age, while also extending maximum lifespan, though this wasn’t always the case for females. However, a repeat study found that Acarbose was only half as effective in males when given at 16 months of age, and had no significant effect on the median female lifespan.
Examples: Alogliptin, Linagliptin, Sitagliptin, Saxagliptin
Mechanism of action: These drugs inhibit an enzyme called dipeptidyl peptidase-4 (DDP-4). The inhibition of DDP-4 prevents the enzyme from inactivating another protein called GLP-1 (glucagon-like peptide-1). GLP-1 then binds to receptors in the pancreas, leading to increased insulin release and a reduction in the release of glucagon, a hormone that has the opposite effect to insulin.
Mechanism of action: Bile acid sequestrants were initially developed to treat high cholesterol, but have also been found to reduce blood sugar levels, though how exactly they do this isn’t fully understood. They bind bile acids in the gut, preventing their reabsorption. This leads to an increase in bile acid synthesis. Bile acid doesn’t just aid digestion, but also plays a signalling role in the gut, through which it may affect production of glucose in the liver, as well as the secretion of hormones that affect blood sugar.
Mechanism of action: Dopamine agonists bind and activate receptors for the neurotransmitter dopamine in the brain. This leads to an increase in insulin sensitivity, meaning less insulin is needed to remove glucose from the blood.
Examples: Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin
Mechanism of action: These drugs work by blocking sodium-glucose cotransporter 2, a protein in the kidney tubules that reabsorbs sodium and glucose into the blood. By blocking this channel, more glucose is excreted into the urine, resulting in a reduction in blood sugar.
Canagliflozin is one of the diabetes drugs that is of interest in the field of ageing research. An ITP study has shown that canagliflozin can increase median lifespan in male mice by 14%, and increase maximum lifespan by 9%, but has no benefit for females.
Examples: Semaglutide, Exenatide, Liraglutide, Dulaglutide, Lixisenatide
Mechanism of action: Glucagon-like peptide-1 (GLP-1) agonists bind to GLP-1 receptors found on beta cells in the pancreas. This stimulates the secretion of insulin, which lowers blood sugar.
Mechanism of action: Amylin mimetics mimic the activity of amylin. Amylin is a hormone that is secreted alongside insulin by pancreatic beta cells. Amylin has a synergistic role with insulin. It slows the emptying of the stomach and reduces the secretion of enzymes and acids necessary for digestion. It also inhibits glucagon, a hormone with opposite effects to those of insulin. The result of these effects is that blood sugar does not rise as much after ingesting a meal, meaning that less insulin is required to control it.
Time will tell whether any of these drugs are able to extend the lifespan of humans. While some (like metformin) have been relatively well studied in mice, establishing that a drug extends human lifespan is much harder. Efforts are nevertheless being made, notably the TAME trial – a series of clinical trials aimed at studying whether metformin can delay the onset of age-related diseases in older individuals.
Canagliflozin extends life span in genetically heterogeneous male but not female mice: https://doi.org/10.1172/jci.insight.140019
Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males: https://dx.doi.org/10.1111%2Facel.12170
Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer: https://doi.org/10.1111/acel.12496
Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls: https://doi.org/10.1111/dom.12354
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