A few days back, I pointed out research that indicates brain cells increasingly become senescent with age. This is a challenge: we want to get rid of senescent cells and prevent their buildup because the harm they cause contributes to degenerative aging, but the obvious way to do that is through targeted destruction via one of the many types of cell-targeting and cell-killing technologies presently under development. This is fine and well for tissues like skin and muscle, in which cells turn over and are replaced - but in the brain and nervous system there are many small but vital populations of cells that are never replaced across the normal human life span. The cells you are born with last a lifetime, and some fraction of those cells contain the data that makes up the mind.
Thus it begins to seem likely that we can't just rampage through and destroy everything that looks like a senescent cell: possible therapies to address cell senescence as a contribution to aging will have to be more discriminating, and so more complex and costly to develop.
Following on in this topic, I noticed an open access paper today that examines the role of cellular senescence of astrocyte, the support cells of the brain, in Alzheimer's disease (AD). Unlike the research I noted above, the biochemical signatures of senescence examined here are the same as those used in last year's mouse study showing benefits resulting from a (necessarily) convoluted way of destroying senescent cells as they emerge - which of course starts the mind wandering on what might be going on in the brain of these mice. Astrocytes can perhaps be replaced without harming the mind or important nervous cells, but what about other cells in the brain?
In any case, here is the paper:
A recent development in the basic biology of aging, with possible implications for AD, is the recognition that senescent cells accumulate in vivo. Although senescent cells increase with age in several tissues, little is known about the potential appearance of senescent cells in the brain. The senescence process is an irreversible growth arrest that can be triggered by various events including telomere dysfunction, DNA damage, oxidative stress, and oncogene activation. Although it was once thought that senescent cells simply lack function, it is now known that senescent cells are functionally altered. They secrete cytokines and proteases that profoundly affect neighboring cells, and may contribute to age-related declines in organ function.
Astrocytes comprise a highly abundant population of glial cells, the function of which is critical for the support of neuronal homeostasis. ... Impairment of these functions through any disturbance in astrocyte integrity is likely to impact multiple aspects of brain physiology. Interestingly, astrocytes undergo a functional decline with age in vivo that parallels functional declines in vitro. We demonstrated that in response to oxidative stress and exhaustive replication, human astrocytes activate a senescence program.
The importance of senescent astrocytes in age-related dementia has been the subject of recent discussion, but to date, there is little evidence to suggest that senescent astrocytes accumulate in the brain. In this study, we examined brain tissue from aged individuals and patients with AD to determine whether senescent astrocytes are present in these individuals. Our results demonstrate that senescent astrocytes accumulate in aged brain, and further, in brain from patients with AD.
Furthermore, since Aβ peptides induce mitochondrial dysfunction, oxidative stress, and alterations in the metabolic phenotype of astrocytes; we examined whether Aβ peptides initiate the senescence response in these cells. In vitro, we found that exposure of astrocytes to Aβ1-42 triggers senescence and that senescent astrocytes produce high quantities of interleukin-6 (IL-6), a cytokine known to be increased in the [central nervous system] of AD patients. Based on this evidence, we propose that accumulation of senescent astrocytes may be one age-related risk factor for sporadic AD.
As I mentioned in the last post on this subject, this all seems to point to the likely need for ways to reverse cellular senescence, not just selectively destroy senescent cells - at least for some populations of nerve cells. One open question here is whether fixing all the known fundamental forms of cellular damage (as described in the Strategies for Engineered Negligible Senescence) would be sufficient to achieve this end.