Given a sufficiently comprehensive method of destroying senescent cells, it doesn't much matter which populations of senescent cells contribute to which age-related diseases. None of these errant, lingering cells are wanted, and the agenda should be to get rid of them all. With the possible exception of Oisin Biotechnologies' platform, however, none of the existing approaches to senolytic therapies can kill even a majority of senescent cells in a majority of tissues. Small molecule drugs in particular tend to be tissue-specific to meaningful degrees.
In this context of imperfect and selective therapies, it is important to know the degree to which a targeted population of senescent cells is relevant to a specific age-related condition. The open access paper here is an example of this type of research, in which the authors rule out some of the possible contributing populations of senescent cells as causes of osteoporosis. It is interesting, but I feel that this sort of thing is a transitory concern, and will evaporate for all but academic interests given the advent of highly effective senolytic therapies that work in all tissues.
Soon after the attainment of peak bone mass, the balance between bone resorption and bone formation begins to progressively tilt in favor of the former, in both women and men. Age-related bone loss in mice is associated with an increase in the number of osteoclasts, the cells responsible for degrading the bone matrix. Nonetheless, a decline in bone formation is the seminal culprit of skeletal aging in both humans and rodents. A decrease in the number of osteoblasts, the cells that synthesize the bone matrix, underlies the loss of bone in aged mice. Osteoblasts differentiate from mesenchymal progenitors; the number of these osteoprogenitors declines with advancing age and this decline is associated with increased markers of cellular senescence.
Osteocytes, former osteoblasts buried in the bone matrix, are postmitotic and the most abundant cell type in bone. Osteocytes modulate bone resorption and formation. Earlier findings have elucidated that, like other postmitotic cells, osteocytes in the bone of aged female and male mice show markers of senescence. Several, but not all, senescent cell types exhibit high levels of the cyclin inhibitor p16. For example, senescent osteocytes have increased levels of p16, while senescent osteoblast progenitors have elevated levels of p21, but not p16.
Selective elimination of cells expressing p16 in mouse models increases life- and healthspan. Currently, two of such models have been described: the INK-ATTAC and the p16-3MR mice. Using the p16-3MR model, we have effectively depleted senescent cells in the skin, lungs, muscle, and bone marrow, including senescent hematopoietic and muscle stem cells, and suppressed the senescence-associated secretory phenotype (SASP) in aged mice. It has been found that elimination of p16-expressing cells in 20-month-old mice for a 4-month period, using the INK-ATTAC transgene, increases bone mass. These findings support the notion that senescent cells contribute to age-related bone loss.
However, the identity of the senescent cells that are responsible for skeletal aging remains unknown. Likewise, the extent to which elimination of p16-expressing cells rescues skeletal aging is unknown. Here, we investigated the skeletal effects of long-term ablation of senescent cells using p16-3MR mice - an alternative to the INK-ATTAC model of p16-expressing cell elimination. The key objectives of this work were two: first, to eliminate p16 senescent cells from 12 to 24 months of age, the time period during which C57BL/6 mice experience a dramatic age-related loss of bone mass, and determine whether the experimental maneuver could prevent the loss of bone. And second, to eliminate p16 senescent cells from 20 to 26 months of age in order to determine whether this intervention could restore bone mass in mice that had already lost it.
The activation of the p16-3MR transgene greatly diminished p16 levels in the brain, liver, and osteoclast progenitors from the bone marrow. The age-related increase in osteoclastogenic potential of myeloid cells was also abrogated. However, this did not alter p16 levels in osteocytes - the most abundant cell type in bone - and had no effect on the skeletal aging of p16-3MR mice. These findings indicate that the p16-3MR transgene does not eliminate senescent osteocytes but it does eliminate senescent osteoclast progenitors and senescent cells in other tissues. Elimination of senescent osteoclast progenitors, in and of itself, has no effect on the age-related loss of bone mass. Hence, other senescent cell types, such as osteocytes, must be the seminal culprits.