BIOTECHNOLOGY


One of the best starting points


for understanding how we age is to look at other creatures in the animal kingdom, according to Rolf Bodmer, program director at Sanford Burnham Prebys Medical Discovery Institute in San Diego. How is it, for example, Bodmer asks, that the nematode worm C. elegans lives for only around two weeks, while giant turtles can sometimes live for upwards of two centuries? It’s these similarities and


differences, researchers say, that will provide insights on how to control and perhaps even slow or reverse the process in humans. One clue, Bodmer suggests for example, might lie in the ‘fidelity of cell replication’, which is ‘inherent to different organisms or species’ – and varies from one error in 10,000 to one in many millions. Bodmer’s own work has focused


on Drosophila fruit flies, which are easily reared in the lab and have a lifespan of around 40-50 days. Interestingly, they also have a similar heart structure to humans, and share many of the same heart genes and proteins. In 1993, the group identified a specific gene that appears to prevent the flies from developing heart disease (Development, 1993, 118, 719) – one of the chief life- threatening diseases linked to ageing. Later, the homologue of this ‘tinman’ gene, so-called after the character in The Wizard of Oz, was also found in humans. In more recent work to slow heart


ageing, Bodmer reported that the group has demonstrated the ability to impede the development of arrhythmia or irregularities in heart beat in fruit flies. ‘We figured out that if we reduce insulin signalling – which is important in homeostasis – we can reduce the ageing process in an otherwise normally ageing body,’ he said. The work follows on from a collaboration with Nasa to send the flies into space, and examine how prolonged exposure to microgravity affects heart function and structure. To date, the vast majority of work


on ageing has been directed against the diseases and consequences associated with growing older. While not ideal, this focus on what David refers to as the ‘leaves and branches’ – rather than the ‘trunk or roots’ – of the matter is currently necessary both for regulatory reasons - as well as for ease of funding.


We think of ourselves as a spare parts business by targeting and replenishing diseased or damaged tissues. Like when your car tyres need replacing every few thousand km


Osman Kibar Samumed Unity itself is initially directing its 353


Number of methylated cytosine bases in DNA in Steve Horvath’s epigenetic ‘clock’, which predicts a person’s age from a blood sample with an accuracy of one to three years


Senescent cells are in effect cells that have stopped dividing, usually after around 50 cycles of cell divisions when they have accumulated substantial damage and no longer make or repair new tissues.


efforts on what David describes as a very important branch: a mechanism of ageing called cellular senescence, he explained; thought to be a key driver of many age-related diseases, including osteoarthritis, glaucoma and atherosclerosis. Senescent cells are in effect cells that have stopped dividing, usually after around 50 cycles of cell divisions when they have accumulated substantial damage and no longer make or repair new tissues. But after these cells become senescent, they secrete pro- inflammatory molecules that slow healing and promote damage and stiffness to nearby tissue. Recent studies have shown that eliminating senescent cells has multiple beneficial effects in animal models. In the laboratory, for example, David pointed out that researchers have found that genetically identical mice whose senescent cells have been removed lived 35% longer than their siblings. (D. J. Baker et al, Nature, doi: 10.1038/ nature16932.). A mouse equivalent to 70 human years of age was ‘blind and frail and had cardiac dysfunction,’ while its ’70-year old’ sibling without senescent cells not only lived longer but also ‘behaved younger’. But if senescence is so harmful,


then why does it occur in the first place? The reason, David believes, is as an ‘emergency brake’ to prevent cancer: to stop damaged cells from dividing and going on to develop malignancy. This damage is cumulative over time; it arises due to injury or other stresses in the environment. In other words, David said:


‘Ageing is something that’s done


to an otherwise genetically stable system…I believe ageing is a series of optimisations by Nature to do good – with the unintended consequences of later in life things go bad.’ At Unity, he explained that


the goal is to selectively remove senescent cells by using small molecules, particularly in regions of the body that show signs of wear and tear, like the eyes and joints, where they have a tendency to accumulate. While Unity’s small molecule drugs are designed to slow or reverse disease, he stresses they shouldn’t pose any extra cancer risks as they won’t stop senescent cells from accumulating – which means patients will need repeat treatment every few years.


Earlier in 2017, the company’s


first-in-class ‘senolytic’ molecule UBXO1O1 was also reported to slow the progression of osteoarthritis and induce cartilage production in mice (Nature Medicine, doi:10.1038/ nm.4324). The firm hopes to progress the compound into the clinic in the next few months, while other targets include atherosclerosis, eye diseases and kidney diseases. ‘Osteoarthritis is the reason it


hurts to be old,’ David said. ‘If it didn’t hurt to be 80, people could reorganise their lives. There would be enormous cost savings for national healthcare budgets.’ San Diego based biotech Samumed, meanwhile, also has its sights on osteoarthritis as one of the important targets for its health span extending therapies. Samumed’s own OA drug has already demonstrated efficacy in the clinic and is set to go into Phase 3 trials in early 2018. In this case, however, the firm is targeting a different strategy geared around so-called Progenitor Stem Cells (PSCs), said Samumed CEO Osman Kibar. PSCs are cells embedded in


tissues for repair of wear and tear of aged or damaged tissues. ‘As we age these PSCs start going out of kilter so they can’t perform their repair duties for certain tissue types, leading to a range of complications such as loss of cartilage and osteoarthritis,’ Kibar explained. ‘We work on small molecules that target PSCs regulating them towards replenishing and replacing damaged tissues.’ If successful, Samumed’s OA drug could be the first treatment to regrow


28 08 | 2017


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