A paper published in Cell investigated the effects of a peptide to target senescent cells in mice and reported improved kidney function and restoration of fur, suggesting that this could lead to a therapy with potential to reverse certain aspects of ageing.
Prof. Ilaria Bellantuono, Professor of Musculoskeletal Ageing, University of Sheffield, said:
“The development of drugs, which interferes with the causes of ageing and improve health and fitness are a relatively new area of research and have the potential to change the way we treat diseases of older people and keep people healthy for longer. Elimination of old cells has been shown to delay the onset of age-related diseases such as muscle weakness, cataracts, diabetes. It can also be used to boost fitness before undergoing chemotherapy in cancer patients and avoid its debilitating side effects. In this respect the peptide identified in this study is more potent in eliminating old cells compared to previously tested drugs and therefore it is promising. The study shows improvement in some markers of age such as loss of fur or kidney function.
“However, a much more in depth characterization of the function of each organ should be considered before any conclusion can be drawn as to whether this is going to boost health and be useful in any clinical application. Tests for heart, muscle, metabolic, cognitive function should be performed. In addition the potential effects on tumour growth should also be tested to ensure it is not limiting the efficacy of any chemotherapy given to eliminate the tumour. Even when all of these tests will be performed in animal models, the use of this peptide in patients is a long way away. It requires careful consideration about safety, about the appropriate group of patients for whom this peptide can be beneficial in a reasonable period of time so that positive effects can be easily measured at an affordable cost.”
Dr Dusko Ilic, Reader in Stem Cell Science, King’s College London, said:
“The paper addresses an interesting concept – removing senescent cells may improve tissue homeostasis and postpone certain aspects of ageing. They found that a protein named FOXO4 is elevated in senescent cells and is responsible for maintenance of their viability. FOXO4 interacts with a tumour suppressor p53, which is involved in various cellular processes including senescence, DNA repair, and cell cycle arrest. Interfering with the interaction of these two proteins will activate in senescent cells a mechanism that will lead to their death. They synthesized a peptide (small protein) that blocks FOXO4 interaction with p53. Continuous infusions of this peptide, three times a week, to different mouse strains over the extended period reverted some aspects of ageing.
“The finding is impossible to dismiss. Everything is in place, from exact molecular mechanism to in vivo demonstration. However, this is the first such study and there are a lot of unanswered questions that need to be addressed before we can even think about clinical trials in humans. p53 is known as the guardian of genome and interfering with its function is the basis of many cancers. Until more high-quality research is done, it is better to be reserved about these findings. Though, I would not be surprised if manufacturers try to capitalize on this and, in a few years, we could buy this peptide as a supplement over the counter.”
Dr David Clancy, Lecturer in the Department of Biomedical & Life Sciences, Lancaster University, said:
“As we age, cells accumulate damage. Depending on the level and type of damage, cells can undergo cell death or they can enter a state known as senescence; a state which prevents them from dividing but involves the secretion of a number of factors which can be inflammatory locally and more distantly, and can help local tumour cells acquire the ability to spread (metastasis). So as we age, senescent cells increase in number and their effects, particularly inflammatory effects, increase. This age-related inflammatory environment (sometimes called inflammaging) likely contributes to many age-related diseases, neurodegeneration in particular.
“The process is an example of a mechanism that is beneficial while young but harmful when old. It is essential for wound healing, necessary to help young animals survive, but cell senescence contributes to ageing itself in humans, and particularly increases frailty.
“Using a drug designed to make senescent cells undergo cell death, Peter de Keizer and colleagues report senescent cell reduction and some measures of increased functional health in mice. Luckily the target of the drug is present in large amounts in senescent cells but very low levels in other cell types, which means that the drug seemed to be well tolerated by the mice.
“The major effects were seen using short-lived mouse models; one in which cell senescence was induced using an anticancer chemotherapy drug, and a genetically short-lived model which shows a number of effects similar to normal ageing. In these models many measures of functional ageing were improved.
“Although this is early work – the drug regimens reported are limited – normal old mice treated during old age showed increased kidney function and responsiveness to touch however no increase was seen in running wheel activity. We eagerly await reports of more assays of functional health and of lifespan in normal ageing mice.
“The drug is actually a small protein. A potential problem with these types of therapies is that an immune response against the drug may occur, however some have reached the stage of clinical trials and been shown to be effective. So this study may represent the first report of a treatment type which could increase functional health in humans at older ages.”
* ‘Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging’ by Baar et al. will be published in Cell on Thursday 23 March 2017.
Prof. Ilaria Bellantuono: Funding from MRC Arthritis Research UK horizon 2020 and cancer research UK.
Dr Dusko Ilic: No conflicts of interest.
Dr Dave Clancy: No conflict of interests to declare.