The race to develop senescent cell clearance therapies

Author: Nick Dragojlovic, 05/03/16
By Michelle Olive, NHGRI - http://www.genome.gov/pressDisplay.cfm?photoID=20132, Public Domain, https://commons.wikimedia.org/w/index.php?curid=13811269

Confocal microscopy photographs of the descending aortas of two 15-month-old progeria mice, one untreated (left) and the other treated with the FTI drug tipifarnib (right) By Michelle Olive, NHGRI – http://www.genome.gov/pressDisplay.cfm?photoID=20132, Public Domain, https://commons.wikimedia.org/w/index.php?curid=13811269

A growing focus of biomedical research and regenerative medicine is the effort to target the aging process itself, by either slowing or reversing the accumulation of cellular and molecular damage that drives age-related functional decline. The goal is to develop new treatments for age-related chronic diseases, which are the leading cause of death in the developed world.

Take the United States as an example: In 2013, heart disease, cancer, and chronic obstructive pulmonary disease (COPD) were responsible for 53% of total deaths, and chronic diseases account for 86% of health care costs as per this article in Nature Biotechnology. Given the massive societal burden imposed by age-related chronic diseases, it’s not a big leap to infer that treatments that succeed in delaying or reversing the aging process would substantially improve human health, increase life expectancy and generate very large economic benefits

In deciding on whether to fund this type of research, however, governments, foundations and investors face a key question:

Are interventions that target the drivers of aging plausible in the near future, and are they likely to deliver the promised health benefits?

Targeting the Hallmarks of Aging

Programs like the National Institute on Aging’s Interventions Testing Program have had some success in screening compounds for their ability to delay aging in mice by altering metabolism (e.g., rapamycin, which has been shown to delay aging in mice even when administered late in life). A growing number of research groups and companies, however, are focusing on more targeted interventions that aim to clear and repair the specific forms of molecular and cellular damage that drive the aging process.

In a comprehensive review in Cell, López-Otín and colleagues outlined the nine “hallmarks of aging,” which include epigenetic alterations, stem cell exhaustion, and cellular senescence. The extent to which each hallmark contributes to the overall aging process (which is defined as “the time-dependent functional decline that affects most living organisms”) is unclear, but there is growing evidence that cellular senescence is a key driver of aging and that removing senescent cells can reverse some of the functional decline associated with aging.

Senescent Cell Clearance and Aging

When cells become senescent (due to telomere attrition, DNA damage, or other types of cellular stress), they stop dividing. This provides a useful way of halting the proliferation of potentially cancerous cells. Unfortunately, senescent cells are distinctive in other ways – notably, they begin to release a set of pro-inflammatory proteins, growth factors and proteases (collectively referred to as the “senescence-associated secretory phenotype” or SASP) that affect surrounding cells and disrupt tissue structure and function (by, for example, causing local tissue inflammation).

Senescent cells gradually accumulate in mammals over the course of their lifespan, and this accumulation has been associated with age-related diseases. It is only in the last few years, however, that hard evidence has emerged of the causal effect of senescent cell accumulation on physiological decline.

In a landmark 2012 study, the Mayo Clinic’s Darren Baker and colleagues established the first proof of concept that senescent cells cause age-related functional decline. They genetically modified progeroid mice – which appear to age rapidly, much like humans affected with progeria – in a way that allowed them to selectively remove a class of senescent cells from the mice’s bodies by administering a drug that induced apoptosis (cell death) in these cells. Crucially, they found that clearing senescent cells on a regular basis delayed the development of age-related conditions in the mice’s skeletal muscle, fat and eyes.

While this study provided a proof of concept using a clever design, the extent to which the findings were generalizable to natural aging was unclear, so Baker and colleagues conducted a follow-up study using naturally-aged mice, published this past February in Nature. They found that clearing senescent cells every two weeks increased the median lifespan of male and female mice by up to 35%, and extended their healthspan by delaying the onset of cancer and attenuating age-related deterioration in the kidneys, heart and fat – all with no observed side effects.

Senolytic Therapies Under Development

The implication of this study for regenerative medicine is that regularly clearing senescent cells might lead to an improvement in a broad range of age-related chronic disorders in humans. Given the promising results in mice, it is no surprise that a number of research groups and companies are searching for drugs that selectively destroy senescent cells (so-called “senolytic” drugs) or inhibit the production of SASP.

The race is on, and at least two biotechnology companies have been founded to tackle the problem: Oisin Biotechnologies, which is pursuing an innovative gene therapy approach; and, UNITY Biotechnology, a company backed by the Mayo Clinic and ARCH Venture Partners that has leading senescent cell researchers like Judith Campisi as advisors. Other companies are sure to follow in short order now that senescent cells have been demonstrated in an animal model to be a promising target for regenerative medicine. It may take a number of years for senolytic drugs to make their way from animal models to the clinic, but when they do become available, they have the potential to be transformative.

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Nick Dragojlovic
Nick Dragojlovic is a health services researcher at the University of British Columbia's Faculty of Pharmaceutical Sciences. He has previously held postdoctoral fellowships at the University of Calgary and at UBC, and has received funding from the Canadian Institutes of Health Research and the Michael Smith Foundation for Health Research. He holds a BA from Yale University and an MA and PhD from UBC. Nick is particularly interested in the use of alternative finance mechanisms to support scientific research, and covers the topic on his blog: Funded Science
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