Evidence of a Senescent Cell Population for which Elimination Might be Problematic
Senescent cells accumulate throughout the body with age. They are constantly created and destroyed throughout life, but the balance between creation and destruction is upset with age, leading to an accumulated burden of cellular senescence. These cells secrete a potent mix of signals that produce chronic inflammation, disrupt tissue structure and cell function, and encourage other cells to also become senescent. The more senescent cells, the worse the impact. They are an important contributing cause of aging.
Targeted removal of senescent cells has been shown to meaningfully reverse the progression of age-related disease for numerous conditions in animal studies. Further, it extends life span in mice. These results are generally easily replicated and quite robust; we should take it as well settled that clearance of senescent cells in mammals produces literal rejuvenation. Even so, some researchers have suggested that senescence in old tissues might be in some way adaptive, preserving cells that would otherwise not be replaced. Perhaps the balance of negative impacts favors their retention rather than destruction, even though these cells cause harm in their senescent state. This argument has been put forward for senescent T cells of the adaptive immune system, for example, given that new T cells are barely created at all in late life, and even though there are plenty of concrete examples of senescent T cells causing harm.
The proposition of cellular senescence being, on balance, better than the alternative of losing the cells in question entirely cannot be universally (or even broadly) true throughout the body, given the existing animal data on clearance, but perhaps it is true for smaller populations of senescent cells in specific tissues. In the paper I'll point out today, researchers suggest that a class of liver endothelial cells are one such population. This must still be balanced with the greater weight of research suggesting that global clearance of senescent cells is unambiguously beneficial, but as noted here, there are questions as to just how global that global clearance is for various approaches. Populations that are beneficial may be skipped by one or another type of therapy, a situation that could lead to roadblocks in the development of therapies down the line. We shall see.
Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan
Substantial evidence has demonstrated that the accumulation of senescent cells can drive many age-associated phenotypes and pathologies. For example, senescent cells accumulate in adipose tissue of patients with diabetes and age-related metabolic dysfunction, in osteoarthritic joints, in the aorta in vascular hyporeactivity and atherosclerosis, and in the lungs in idiopathic pulmonary fibrosis. While selective elimination of these senescent cells confers notable benefits in some tissues, recent studies have also described beneficial roles for senescent cells, raising the question of the differential roles of these cells in various tissues.
Senescence-ablator mouse models have pioneered the field of in vivo senescence studies. With the use of one such model, known as the INK-ATTAC mouse, that is based on a 2,617 base pair fragment of the p16Ink4a gene promoter, it has been proposed that removal of p16-expressing cells results in life extension in mice. The concern, however, is whether the reporter construct with a part of the p16 genomic sequence fully resembles endogenous p16 gene expression, especially with aging. This is further supported by the fact that some p16-expressing cells are not efficiently removed by the INK-ATTAC system in several tissues, including the liver, colon, and T lymphocytes. Thus, it is unclear whether there are important senescent cell types in tissues where the INK-ATTAC system does not work and what impact their removal has on health span.
Here, we generated two knock-in mouse models targeting the best-characterized marker of senescence, p16Ink4a. Using a genetic lineage tracing approach, we found that age-induced p16High senescence is a slow process that manifests around 10-12 months of age. The majority of p16High cells were vascular endothelial cells mostly in liver sinusoids (LSECs), and to lesser extent macrophages and adipocytes. In turn, continuous or acute elimination of p16High senescent cells disrupted blood-tissue barriers with subsequent liver and perivascular tissue fibrosis and health deterioration. Our data show that senescent LSECs are not replaced after removal and have important structural and functional roles in the aging organism. In turn, delaying senescence or replacement of senescent LSECs could represent a powerful tool in slowing down aging.
Well, if we have senescent neurons they might better nee kept. For the rest i am not convinced. Of course if within senecent cells we have a quiescent group that doesn't divide but otherwise is harmless and even functional they might be kept.
Pulmonary hypertension is an important adverse event associated with senolytic dasatinib. Persistent pulmonary hypertension is present in up to one third of patients even after cessation of dasatinib. See: Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension. (https://europepmc.org/article/pmc/pmc5962749 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664660/)
Consequently, I think that senolytics should not be used as monotherapy, but in combination with methods of replacing the loss of old cells by increasing the number of younger progenitor cells. A better approach would be to activate the filling of the "released space" by stimulating endogenous replacement mechanisms. But in the adult body, such a replacement is usually fibrous scar tissue, instead of functional tissue. In industrialized countries, chronic fibrotic diseases account for more than 45% of all deaths.
Therefore, methods for activating the division of progenitor cells while suppressing the formation of fibrous tissue are necessary. One of these methods is proposed in my article: "Can a combination of senolytics with ROCK inhibitors and 5-LOX inhibitors contribute to tissue rejuvenation? A Review of the Literature and a Working Hypothesis." https://docs.google.com/document/d/10onyRyohpZPwRnPUyMpBSfuGWOlqS489Xe5WEZNrVDQ/edit?usp=sharing
@Dmitry Dzhagarov: I think it's too premature to assert that a side-effect of dasatinib is a side-effect of any senolytic.
@Dmitry Dzhagarov: Dasatanib is a nonspecific RTK inhibitor, and as a consequence of that non-specificity has all sorts of off target effects. It's totally different from bcl-xL inhibitors being looked at by Unity, and the p16 targeted caspase expression system that Oisin is looking at. While the bcl-xL inhibitors have issues with platlete toxicity, a recent paper (1) which employed a navitoclax based PROTAC was able to mitigate that side effect.
It's way to early to say that these side effect is a general consequence of senolysis, and it's also worth noting that chemotherapy regimens using dastanib differ radically in terms of dosages and duration and other drugs used in combination from the most common senolytic combination of D+Q.
1. https://www.nature.com/articles/s41467-020-15838-0
Hi, Antonio & Dylan Mah!
It is a pity that you did not pay attention to the topic of discussion: "Evidence of a Senescent Cell Population for which Elimination Might be Problematic" Alas, there are a number of cells, for which (due to the high specialization of their functions), the loss is irreplaceable or extremely limited. For example:cells of the heart muscle (lose their ability to regenerate a week after the birth of a baby), some cells of the brain, some eye cells, hair stem cells (gray hair is not reversible in the elderly). You need to think about how to rejuvenate them or replace them with young ones without losing the quality of their functions. This is the bottleneck of senolytic therapy. I am not an opponent of the senolytics, I urge you to look for ways to maximize the benefit of their use.
@Dmitry Dzhagarov: I am well aware of the issue, but your specific assumption on dasatanib regarding the persistent side effects isn't necessarily correct; it's a reasonable hypothesis that cell populations are being lost that can't be renewed, but that's also related to the drug's mechanism of action.
The specific population of senescent cells being interrogated in this study incidentally were spared by dasatanib + quercetin. The most desirable senolytics will be those that selectively eliminate problematic populations of cells that are replaceable without harming those that are not.
This could potentially be combined with a strategy for blocking the sensecent phenotype in those populations that are not readily replaced, or some sort of regenerative medicine strategy for inducing replacement of those tissues, but regenerative medicine is an entirely different area of research from senescence research, the people working on these respective sides of the problem are going to be totally different.
I've read a half dozen arguments for why we may "need" stem cells. To my mind, none of them hold up. I plan to get rid of all of the senescent cells in my body. (Anyone who wants more stem cells is welcome to take some of mine :) )
Re: the suggestion that it's better to have senescent T cells in our bodies than no T cells at all -- fortunately those aren't our only two choices. The most effective way to clear senescent cells out of the body is with a five day fast or fasting mimicking diet. Such diets destroy senescent cells (and senescent mitochondria). Then when we start eating again, the body creates a flood of new stem cells, which can turn into T cells if needed.
(The notion that "we can't create new T cells" may be generally true, but in this context it's inaccurate. Stem cells can turn into any sort of cell that's in short supply, including T cells.)
The other argument for keeping senescent cells is that they're so sickly and decrepit that they can't become cancerous. I'd rather take my chances with cancer than have a body that's accumulating more and more decaying, half-alive cells leaching toxins into surrounding tissues. Senescent cells may not become cancerous, but healthy young cells (like the ones created by the body after a fast) don't either.
Finally, as the author points out, lab animals who have had their senescent cells removed live longer. I haven't seen any studies suggesting that they go on to die of cancer. But even if they did, I'd still opt to have my senescent cells deleted. If we live an extra 10 years because of removing senescent cells, then get cancer and die, we've still lived those extra years.
I think this paper has an important caveat - they drove their suicide gene using what was probably a more constitutive promoter than that used by comparable papers in the literature. Specifically, they used the native p16 promoter instead of the p16 promoter fragment used in other papers, such as those of the Campisi lab. p16, aside from its association with senescence, is a cell cycle gene - it's quite feasible that their p16-eliminating system was also killing healthy cells progressing through the cell cycle. If so, this would would be sufficient to account for the toxicity they reported.