Targeting death

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, which is looking at ways of modifying disease in old age, and the first phase of the Frailomic initiative, 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

Notwithstanding the search by alchemists throughout the centuries for an elixir of youth, we have become accustomed to the pharmaceutical companies creating solutions to the causes of all our fevers and other morbidities. In the case of anti-ageing or senolytic drugs, the industry has thus far failed to uncover mechanisms they can exploit. Nevertheless, over the last 20 years we have seen several candidates given serious consideration. Estimates suggest that as many as 50 contenders are currently being considered. For example, the drug metformin, long available for treatment of type 2 diabetes, has demonstrated some anti-aging properties. One study showed that diabetic patients treated with metformin lived longer than diabetics not being treated with metformin (and age-matched unmedicated non-diabetics). However, the possible action of metformin is unknown and not a targeted mechanism and thus its action may reflect some unrelated benefit.

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. 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. 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. 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 eliminatino 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 cells4) and pharmacological (i.e., 'senolytic' compounds) have been used to attack senescent cells. 

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. In a decades-old experiment, where the circulatory systems of young and old rodents are connected, it was found that the older mice benefited. It has been proposed that chemical factors in young blood work on stem cells in the older animals. Stem cells are kept in reserve by the body as means to repair and regrow damaged tissue. Like every other part of the body, they wear out as an animal ages. But something in the youngsters’ blood seems to restore their ability in older mice to proliferate and encourages them to repair damage with the same vigour as those belonging to a younger animal would.

An approach to anti-ageing could simply involve infusing blood from younger donors. Several commercial operations are already offering this option if you have the right money – however, there is no clinical proof that it works in humans. One company has already looked at the potential benefits in patients with Alzheimer’s disease. Preliminary results appear to indicate that the procedure is safe but there is no evidence of it having influenced the disease. Another lingering question is whether it’s the blood that’s helpful, or some combination of factors from an entire body. It is important to remember that the initial evidence for these treatments came from mice physically sewn together. This means that they effectively shared organs and entire bodily system. It is likely to be more than just blood that caused the improvements.

Years of experimenting on animals has shown that caloric restriction is a non-invasive and effective way to slow the biological signs of aging. But, save for a few small and dedicated communities of human calorie-restrictors, it’s hard to convince people to override their biological desire to eat enough food to feel full. There’s good evidence that exercise can slow aging, too, but exercise alone usually isn’t sufficient to make a significant impact. Pharmacological interventions can more easily fit into people’s lifestyles. And properly formulated research is beginning to point at possible targets - there are even a few promising candidates. Although the search for a way to delay human ageing has proven long and elusive, many feel we are standing on the precipice of yet another revolution in lifespan modification. However, as we are only starting to get a grasp of the medicine-of-the-old it seems unlikely that we are ready to understand the medicine of the very, very old and we have yet to fully consider the socioeconomic consequences it may have.

 

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