As our bodies age, our tissues accumulate senescent cells — cells that have ceased dividing but persist, secreting enzymes and other protein signals that damage the tissues in which they reside. Senescent cells are often detected at sites of age-associated pathology, such as atherosclerotic lesions and arthritic joints, suggesting that they play a causative role in aging. Consistent with this idea, eliminating senescent cells in mice extends lifespan and delays the onset of disease.
To date, the role of senescence in the aging of the nervous system—especially the brain—has remained unclear. However, recently published findings from Darren Baker’s research team at the Mayo Clinic strongly suggest that, just as senescent cells promote age-related decline in other tissues, they also contribute to neurodegeneration.
To investigate the relationship between senescent cells and brain aging, Bussian et al. took advantage of a genetically engineered mouse that produces high levels of tau, a protein that forms dense aggregates in Alzheimer’s disease (AD). These tau-expressing mice undergo neurodegeneration and develop cognitive defects reminiscent of human AD patients. The authors then used a standard battery of immunological and histological staining methods to demonstrate that senescent cells did indeed accumulate in the brains of tau mice.
The brain cells that underwent senescence were not neurons, but two other types of cells peculiar to the nervous system: astrocytes, which provide various kinds of metabolic support to nerve cells, and microglia, which are macrophage-like cells the play key roles in the central nervous system’s dedicated immune system. Collectively, we’re going to call these cells “glia” for the remainder of the article.
Not only did the senescent glia accumulate in diseased brains, they did so significantly earlier than the other signs of disease: tau aggregates, neurofibrillary tangles, neurodegeneration, and cognitive decline. This was consistent with, but not conclusive evidence of, a causative role for senescence in tau-related disease (hereafter “tauopathy,” a term that I swear I did not make up). At this point in the story, however, the evidence remained circumstantial.
One way to determine whether senescent cells are positively contributing to some outcome is to eliminate the senescent cells and see whether the outcome disappears; Bussian and co-workers did just that. Elimination was achieved in two ways: first, by introducing a transgene that enables selective killing of senescent cells with an otherwise innocuous drug, and second, using a relatively new class of pharmaceutical called a “senolytic”, which destroys senescent cells directly without the need for prior genetic manipulation.
The transgene approach yielded dramatic results: getting rid of senescent cells abolished the molecular hallmarks of early tauopathy, thereby rescuing cognitive function. Mice treated with the senolytic drug also exhibited diminished tau aggregation; however, the authors appear not to have investigated whether they benefited cognitively.
The results convincingly argue that, in addition to its now well-established role in age-related pathology throughout the body, senescence also contributes to brain aging. Importantly, notwithstanding decades of research into human neurodegeneration more generally, the ultimate causes of these disorders remain mysterious, so the a novel causal connection between senescence and tauopathy is likely to attract a great deal of attention across multiple fields.
The findings also suggest, albeit less strongly, that the senolytic compound the authors used can cross the blood–brain barrier, a rare feat among pharmaceuticals that will doubtless excite drug developers. I qualify the statement because one feature of senescent cells is that they act at a distance by secreting protein factors into the extracellular milieu — if these factors were to circulate in the blood, one could imagine that a drug’s effect on senescent cells elsewhere in the body might affect senescence-related phenotypes in the brain.
When discussing the advent of anti-aging medicine, one of the (clever) questions I often field is the following: What if we were able to delay or even prevent aging in every tissue but the brain? It’s a chilling thought, raising the spectre of people with intact, fit bodies and youthful faces, slowly losing cognitive function as dementia marches inexorably forward.
From that standpoint, the Baker lab’s findings are particularly optimistic, because they show that is at least possible that the same principles we’re applying to aging-related changes in the peripheral tissues of the body can also boost function and prevent disease in the central nervous system.