Targeting death

October 26, 2017

- Tim Hardman

Many of the increasing number of elderly in our population are eager to avoid the frailties and comorbidities associated with ageing.With little scientifically recognised treatments available to counter the inevitable effects of time many are resorting to lifestyle modification. Others are looking for more direct approach that not only include drugs to alleviate the effects of ‘the deadly quintet’ of cancer, cardiac disease, respiratory disease, dementia and diabetes but claim to target ageing itself. In this snapshot of current development in the science of ageing we mark conclusion of the clinical phase of the MID-Frail study [1], which is looking at ways to change diseases that happen in old age, and the start of the Frailomic initiative [2], investigating inherent markers for the development of frailty. Both initiatives are funded by multimillion Euro grants from the European FP7 Framework and being run by Niche Science & Technology Ltd.

Elixirs of youth

Although alchemists have been looking for an elixir of youth for hundreds of years, we are used to drug companies finding cures for all of our illnesses and fevers. As of now, the drug business has not found any ways to take advantage of mechanisms that work against ageing or senolytics. Still, over the last 20 years, we've seen several candidates get real attention. It is thought that as many as 50 candidates are being considered now. For instance, the drug metformin, which has been used for a long time to treat type 2 diabetes, has been shown to slow down the ageing process. One study found that diabetics who were given metformin lived longer than diabetics who were not given metformin and age-matched non-diabetics who were not taking any medicine. However, no one knows how metformin might work because it is not a targeted mechanism. This means that its action may be due to a benefit that is not linked to diabetes.

In contrast, rapamycin, originally developed to suppress the immune system following organ transplant, hits the mTOR pathway. Inhibition of mTOR extends lifespan in model organisms and confers protection against a growing list of age-related pathologies [3]. Several inhibitors of this pathway are already clinically approved for other uses, and others are under development. Although adverse side effects currently precludes their use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies.

We know that certain experimental cancer drugs undergoing clinical trials, such as navitoclax and obatoclax, have some senolytic properties. Another heartening breakthrough came in 2013 with the isolation of a protein, GDF11, present in young mice, but not their elderly counterparts and found to reduce age-related thickening of the heart of aged mice [4]. It was also shown to improve their physical performance as well. This year, another protein, TIMP2 was shown to counteract some of the mental effects of aging in mice. However, it is important to remember that human aging encompasses progressive changes in multiple organ systems involving a broad range of changes in poorly understood biological changes and unspecific targets. One would be fair in concluding that a pharmacological approach to minimize aging is unlikely to rely on a single target.

A recent proposal has been the removal of what has been termed 'zombie' cells [5]. Eliminating these 'senescent' cells could possibly to forestall many of the ravages of age. Their discovery set off a spate of similar observations confirming that their elimination can alleviate, or even prevent, certain illnesses and extend the lifespan of normally ageing animals. When a cell enters senescence — and almost all cells have the potential to do so — it stops producing copies of itself, begins to release a myriad of proteins, and cranks up anti-death pathways. A senescent cell is in its twilight: not quite dead, but not dividing as it did at its peak. In particular, genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells 4) and pharmacological (i.e., 'senolytic' compounds) have been used to attack senescent cells [6].

Frankenstein and Dracula

One possible way to address the multi-target multifactorial nature of ageing could be to intervene at a biological rather than a biochemical/pharmacological level. Ignoring the obvious references to Frankenstein (blood being an organ) and vampires, the possibility raised following experiments with parabiotic mice and blood exchange have shown interesting results [7]. In a test done decades ago, where the circulation systems of young and old mice were linked, it was discovered that the older mice did better. Some people think that chemical factors in young blood do something to stem cells in older animals. The body stores stem cells in case it needs to fix or grow new tissue that has been damaged. They wear out with age, just like the rest of the body. However, something in the blood of young mice seems to make older mice's cells able to reproduce again and fix damage with the same vigour as cells from a younger animal.

Getting blood from younger donors could be a simple way to slow down ageing. Several businesses already given this option to people with the right amount of money, but there is no clinical proof that it works on people. One company has already investigated how it might help people with Alzheimer's disease. Early results seem to show that the treatment is safe, but there is no proof that it has changed the disease. Another question that keeps coming up is whether it's the blood itself that helps, or if it's a mix of things from the whole body. It's important to remember that the first proof for these treatments came from sewing mice together. What this means is that they shared organs and the whole-body system. The changes were probably caused by more than just blood.

Animal studies over many years have shown that cutting back on calories is a safe and effective way to slow down the biological signs of ageing. But it's hard to get people to go against their natural urge to eat enough to feel full, except for a small but determined group of people who strictly limit their calories. There is also strong proof that exercise can slow down ageing, but exercise alone usually isn't enough to make a big difference. People can more easily fit pharmacological interventions into their daily lives. And study that is done the right way is starting to point to possible targets; there are even a few good candidates. The search for a way to slow down ageing has been long and fruitless, but many people believe we are on the verge of another big step forward in changing people's lives. We aren't ready to understand the medicine of the very, very old yet, though, since we are just starting to understand the medicine of the old. We also haven't thought about the social and economic effects it might have.

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