Piperlongumine is a candidate senolytic agent, demonstrated to selectively destroy senescent cells in cell culture. Its ability to destroy senescent cells in vivo has not yet been confirmed, however, which would normally make it worthy of only academic interest. A sizable fraction of potential therapies fail to make the leap from cell culture to animal study. That said, unlike any of the senolytic candidates so far proven in animal studies, piperlongumine is a natural product, an extract of the long pepper. If it is usefully senolytic in mammals, then the regulatory path to widespread availability is much shorter and much less expensive than is the case for small molecule drugs.
Given this, there is considerable interest among patient advocates in the senolytic ability of piperlongumine in vivo. All it needs is an animal study with suitable accompanying measurements, and then it will be a matter of unleashing the supplement industry to work with regulators, mass manufacture, package, and distribute, giving them something worthwhile to do for a change. Unfortunately, while interesting, this study is not the study that we are still waiting for. The authors show that piperlongumine can achieve exactly the sort of results one would expect of a senolytic for cognitive decline in mice, mention senescent cells in passing, but do not assess whether or not the observed benefits resulted from clearance of senescent cells. This is frustrating, to say the least. The results here should be compared with the effects of the dasatinib and quercetin combination on neurodegeneration in a mouse model of Alzheimer's disease. It adds to the plausibility of piperlongumine as a useful senolytic, but plausibility is not proof.
In both normal aging and under pathological conditions, cognitive decline can diminish the quality of life. In the present study, we found that treatment with piperlongumine (PL), isolated from the long pepper, significantly improved cognitive function in novel object recognition and performance in nest building in 25-month-old female mice. These effects appear to be partly due to the modulation of neuronal activity and neurogenesis in the hippocampus.
PL is a primary constituent of Piper longum, which has been reported to kill multiple types of cancer cells through the targeting of the stress response to reactive oxygen species (ROS). Senescent cells can drive hyperplastic pathology and promote age-related neurodegeneration. Recently, PL has been reported to be a potential novel lead for the development of senolytic agents and the selective depletion of senescence cells as an anti-aging strategy may prevent cancer and aging-related degenerative diseases. Although in this study, we did not investigate the anti-tumour activities of PL in aged mice, PL treatment may be beneficial through the apoptosis of age-related senescence cells.
Cellular senescence is associated with oxidative stress and inflammation. An increase in the expression of GFAP has been the most common change to be observed in astrocytes with aging. The results of this study demonstrated that PL did not affect the size of area occupied by glia, such as microglia and astrocytes, in the hippocampus of the aged mice. We also observed that lipid peroxidation in the hippocampus was not altered in the aged mice. However, previously, we have demonstrated that PL effectively decreases astrogliosis and microglia activation in the parietal cortex in animal models of Alzheimer's disease. The results indicated that the inflammation and microglia activation that was triggered by pathological conditions were effectively suppressed by PL treatment.
In the present study, there were few DCX-positive neuroblasts in the dentate gyrus of 25-month-old female mice, but, the aged mice treated with PL exhibited significantly higher number of DCX-positive cells in the dentate gyrus than in controls. These results suggest that PL may have an effect on neurogenesis by preventing or reversing age-related decline. The precise mechanism of action through which PL improves cognitive function remains unclear. Further studies, therefore, are warranted to investigate the effects of PL on neurogenesis.