Longevity Briefs: An Established Antidepressant Extends Mouse Lifespan

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Ageing is associated with the disruption of many cellular signalling pathways, including calcium signalling. Calcium ions (Ca²⁺) are able to bind to certain proteins and alter their activity, which allows the levels of calcium within cells to influence a wide range of signalling pathways. Cells’ ability to control calcium levels is disturbed in many age-related diseases including cardiovascular diseases, sarcopenia (age-related muscle wasting) and Alzheimer’s. Disrupted calcium signalling is also a key feature of senescent cells – ‘zombie’ cells that have stopped dividing but refuse to die, and that are thought to drive ageing via the harmful signals they release. However, it hasn’t been clear exactly what mechanisms link disrupted calcium signalling to ageing, or to what extent the relationship is causal.

In this study, researchers identify a protein that interacts with calcium that seems to link calcium disruption to ageing. They also identify how calcium levels might become disrupted with age and how this could be reversed with an existing, clinically approved drug.

The discovery:

The researchers began by analysing lung tissue from 12-week-old mice with progeria – a rare genetic disease in which ageing progresses at a greatly accelerated pace (including disrupted calcium signalling). As a result, the average lifespan for human progeria sufferers is only around 14 years. Progeria is not exactly the same as normal ageing because it is the result of a single genetic mutation rather than the gradual accumulation of damage, but it can be a useful model to study how the pace of ageing is influenced. Using protein analysis techniques, researchers were able to identify a specific calcium-binding protein that was more abundant in the lung tissue of progeria mice than in control mice. This protein was S100A6, part of a family of calcium-binding proteins called S100 proteins that are involved in cell division, energy metabolism, inflammation and apoptosis (‘cell suicide’). This is interesting, as all of these processes are closely linked to the ageing process.

By measuring calcium levels in different parts of cells from human progeria patients, researchers were also able to identify exactly how calcium signalling was being disrupted: the endoplasmic reticulum (the organelle cells use to manufacture proteins) was leaking calcium into the rest of the cell, where it activated S100A6. This protein then recruited another protein that breaks down PARP1, an essential DNA repair enzyme. This led to significant DNA damage, with fragments of genetic material leaking outside the cell nucleus and triggering inflammation and senescence in response, with senescence being the primary disease mechanism for progeria. Researchers also found that they could alter this outcome by interfering in various parts of this chain. For example, blocking the channel through which calcium was leaking out of the endoplasmic reticulum prevented S100A6 accumulation, while blocking S100A6 production significantly reduced markers of DNA damage and prevented senescence, suggesting that these were causal mechanisms.

Researchers then treated cells from progeria patients with mianserin (MIA), an antidepressant drug that reduces calcium levels by blocking serotonin receptors. They found that MIA treatment reduced calcium concentrations, decreased S100A6 levels, restored PARP1 expression, and reversed senescence markers. More importantly, they tested this drug in 30 living progeroid mice. Giving these mice 10 mg/kg doses every other day starting at 4 weeks of age increased median lifespan (the age by which 50% of mice are dead) by 27.89% and improved heart, lung, and muscle function compared to untreated mice (though it should be noted, they still lived much shorter lives than mice without progeria).

Finally, researchers looked at whether this mechanism might also be relevant to naturally ageing mice and humans. They found that S100A6 was highly expressed in skin tissue from humans over 70 years old. When eight 20-month-old mice received the same MIA treatment for four months, their median lifespan increased by 17.5% compared to the control group, and they showed improvements in spinal curvature, bone density and motor functions. Similarly, skin cells from 88 and 92-year-old humans treated with MIA showed reduced inflammatory markers and improved cellular health.

The implications:

This research reveals a fundamental mechanism linking calcium dysregulation to ageing and suggests that restoring calcium regulation could be a strategy to extend healthy lifespan in both premature and natural ageing. It also identifies mianserin – a drug already approved for clinical use in treating depression – as a potential anti-ageing drug, though it doesn’t prove that mianserin slows ageing in living humans. Mianserin has a well-established safety profile, but while it is better-tolerated than similar antidepressants, it can still have some rather undesirable side effects and rarely some severe ones, so depending on the necessary dose, it might not be something most people would want to take even if it was shown to slow general ageing.

It should be noted that at just 8 mice in the treatment group, the lifespan experiment in healthy animals was quite small, which weakens the statistical power (though as the difference in median lifespan was very large, good statistical significance was still achieved). Also, it may not be entirely accurate to describe these mice as ‘healthy’, as these were BL/6 mice – a highly inbred strain that develop many health problems that wild, genetically diverse mice don’t get. This is a problem in many mouse studies of ageing and means there is a chance that MIA was only addressing problems specific to BL/6 mouse ageing.