The SENS Research Foundation and the Buck Institute for Research on Aging are both based in the Bay Area, California, and collaborate on a small variety of projects relevant to the development of rejuvenation therapies. This includes clearance of the neurofibrillary tangles that appear in age-related tauopathies, to pick an example announced earlier this year. There is also some cross-pollination of researchers; the aging research field is still a comparatively small community, and people who are or have been involved in SENS rejuvenation research programs can be found scattered throughout. SENS research has been going on for long enough now to produce a fair number of alumni who have gone on to run their own labs or work in other parts of the field. Today the SENS Research Foundation announced an expansion of the Buck Institute collaboration, to include work on the intersection of cellular senescence and immune aging:
SENS Research Foundation (SRF) has launched a new research program focused on dysfunctional white blood cells in collaboration with the Buck Institute for Research on Aging. Judith Campisi, a leading global expert on aging and age-related diseases, will be running the project in her lab at the Buck. Various types of unwanted cells accumulate during aging and affect the function of many systems, including the immune system. Some of these cells are cleared by the immune system, but some are not, possibly leading to a vicious cycle of decline. It is therefore a priority to explore techniques for eliminating these cells and rejuvenating the body, by forcing the unwanted cells to “commit suicide”, and/or by augmenting the cell-killing function of healthy immune cells.
“One of our major goals is to find treatments to augment the aging immune system’s defenses against senescent cells. This collaboration with SRF will enable us to explore a range of hitherto neglected ways to do that. We are extremely proud to be partnering once again with Judith Campisi’s lab and the Buck on this critical project.” This research has been made possible through the generous support of the Forever Healthy Foundation and its founder Michael Greve, as well as the support of our other donors.
Aging is not a linear process; it accelerates as it progresses. As might be expected, this also appears to be more or less the case for the forms of cell and tissue damage that cause aging. When it comes to the state of health and tissues, the difference between 30 and 40 is not the same as the difference between 40 and 50 or the difference between 50 and 60. The downward pace picks up over time. This is characteristic of a self-repairing system, in that there are two primary determinants of the pace of functional decline. The first is the rate at which damage accrues, and the second is the efficiency with which that damage is repaired. The accumulation of lingering senescent cells is a good illustration of the point. Senescent cells are created constantly in our tissues, every time a somatic cell reaches the Hayflick limit on replication, or most of the time when a cell becomes damaged and potentially cancerous. Near all such cells are destroyed quite quickly, either by their own programmed cell death processes, or by the immune system. Unfortunately the immune system – just like all other agents of repair – becomes damaged with age, and its effectiveness declines. As this happens, the rate at which senescent cells accumulate increases.
Of interest in this picture is that at least some of the age-related malfunctioning of the immune system is caused by immune cells becoming senescent and lingering to cause harmful side-effects. While some researchers suggest that this might, at least at first, act as a beneficial adaptation in the face of failing resources, the same can be said of other senescent cells. They help to suppress cancer, at least at the outset when their numbers are small. But by the time they are plentiful, the harms done by their presence far outweigh any help they provide – and in the end, they produce a high degree of chronic inflammation that in fact encourages cancer development. At the present time, it is starting to look like there are multiple classes of senescent cell lingering in the body, sharing a similar set of characteristics, all harmful to health, but possibly different enough to require some tailoring of the therapies presently under development to deal with them.
Since senescent cells attack the effectiveness of the repair system set to watch over them, they encapsulate a cause of death by aging in and of themselves. Even if cellular senescence was the only form of damage that lies at the root of aging, and it is not, it would be able to kill us by crippling the immune system and then going on to produce the failure of organs and other systems as ever more cells in every tissue become senescent. Fortunately the approach of destroying these cells indiscriminately, without caring much about subtypes, seems likely to produce significant benefits based on results in mice to date. Numerous approaches are presently in commercial development. Given that the first of these therapies destroy between a quarter and a half of senescent cells, and only in some tissues, the second generation yet to be developed has considerable room for improvement. That improvement will come alongside the development of better and more discriminating assays for cellular senescence, and this is likely where research into the potential varieties of cellular senescence will prove helpful.
It is also worth considering entirely unrelated efforts to restore immune function in older patients. These are likely to produce sizable benefits to health, as the failure of the immune system is one of the primary causes of frailty in the old. No-one knows whether such a restoration would sweep out a fair portion of senescent cells as well, or how this would compare with targeted therapies for destruction of senescent cells. The only real way to find out is to try it, perhaps initially through the creation and infusion of large numbers of immune cells cultured from a patient sample. Other approaches worth chasing for immune restoration in the old include regeneration of the thymus, the organ that determines the pace at which new immune cells are created, or complete destruction and recreation of the immune system in order to clear out all of the misconfigured and misbehaving cells. In the latter case, the approaches presently used to effect a cure of autoimmune disorders by clearing all immune cells are probably not safe for use in very old people, being essentially chemotherapeutics with harsh side-effects. But it should be possible to produce better methods of targeted cell killing with minimal side-effects, such as via adaptation of the programmable gene therapy approach used by Oisin Biotechnologies to attack senescent cells.