The Immune System Culls Harmful Senescent Cells, and Aging is Accelerated when that Function is Impaired

Cellular senescence is one of the causes of aging. Cells become senescent in response to a variety of circumstances, the most common of which is when a somatic cell reaches the Hayflick limit on replication. Senescence also arises as a result of damage, to shut down cells that might become cancerous. Senescent cells cease to replicate, issue inflammatory signals that attract immune cells to destroy them, and usually self-destruct via programmed cell death mechanisms in any case. The problem with cellular senescence arises from the tiny fraction of senescent cells that evade destruction and linger, polluting surrounding tissue with inflammatory and other signals that evolved for short-term benefit only. When present over the long term, the signals secreted by even a comparatively small number of senescent cells will significantly degrade tissue structure and function, disrupt regeneration, and produce chronic inflammation. This accelerates the development and progression of near all common age-related diseases.

The targeted destruction of senescent cells has been well proven as a rejuvenation therapy in mice in recent years, and human trials are underway for the first senolytic drugs capable of achieving this goal. These initial drugs will be improved upon considerably in the years ahead, as they have side-effects, and only destroy half of the senescent cell burden in some tissues at best, but I expect them to nonetheless produce sizable and broad benefits in older people. Senolytic treatments are a form of repair, clearing away harmful cells that actively maintain a a state of greater dysfunction.

While forging ahead to bring benefits to tens of millions of patients as soon as possible is absolutely the right thing to be doing, there yet remains a great deal to accomplish and investigate as the field expands. On the clinical side of the fence, there are no good commercial assays that quickly and cost-effectively show senescence levels in human tissue, for example. On the scientific side of the fence, it is far from clear as to whether there exist significantly different classes of senescence with meaningful differences in activity and vulnerability to particular senolytic mechanisms. Cataloging past a handful of biomarkers and tissues has barely started. There is also the topic of today's paper, which is the degree to which the presence of lingering senescent cells increases with age because the immune system becomes compromised and falters in its surveillance. Killing senescent cells is a lot easier than restoring the immune system to youthful function, but when that goal is achieved, to what degree will senescence be purged from tissues? The open access paper here is an interesting first attempt to look at the size of this effect.

Impaired immune surveillance accelerates accumulation of senescent cells and aging

Cellular senescence, a central component of aging, is a cell-intrinsic stress response programmed to impose stable cell-cycle arrest in damaged cells, thus preventing them from propagating further damage in tissues. Normally, a sequence of events leads to the clearance of senescent cells and allows regeneration of the tissues that harbor them. In advanced age, however, the efficiency of this process may be compromised, as suggested by the tendency of senescent cells in the tissues of old individuals to accumulate. This accumulation is reportedly conserved across different species, including rodents, primates, and humans. Under such conditions, the beneficial cell-autonomous role of senescence might be outstripped by a negative impact of senescent cells on other cells, an effect mediated via the senescence-associated secretory phenotype (SASP), which has marked pro-inflammatory characteristics.

Senescent cells are subject to immune surveillance by multiple components of the immune system. Senescent cells attract and activate immune cells and serve as highly immunogenic targets for immune clearance. The immune response against senescent cells varies between different pathological conditions. For example, in fibrotic livers senescent cells derived from activated hepatic stellate cells are cleared by natural killer (NK) cells, whereas senescent pre-malignant hepatocytes are eliminated via the adaptive immune system. In other pathological conditions, for example in the case of dysplastic nevi, immune clearance does not occur and senescent cells persist for years. In the context of aging, it is not known to what extent the immune system participates in regulating the number of senescent cells, and whether age-related impairment of immune function contributes to the accumulation of senescent cells in old individuals.

Perforin, a pore-forming protein found in intracellular granules of effector immune cells, is an important mediator of immune cytotoxicity. Upon degranulation, perforin-formed pores enable granzyme penetration and caspase activation to induce apoptosis of the target cell. Perforin-mediated granule exocytosis (but not death-receptor-mediated apoptosis) is essential for the immune surveillance of senescent cells, and disruption of this pathway leads to the accumulation of senescent cells in damaged livers. To investigate the consequences of impaired immune surveillance of senescent cells in aging, we followed the aging process in mice in which granule-exocytosis-mediated apoptosis was disabled as a result of perforin gene knockout (Prf1-/-).

Our data indicates that compared to wild-type (WT) mice, Prf1-/- mice accumulates more senescent cells in their tissues with age. The accumulation of senescent cells in these Prf1-/- mice is accompanied by a progressive state of chronic inflammation, followed by increased tissue fibrosis and other types of tissue damage, as well as compromised organ functionality. The poor health of old Prf1-/- mice is associated with fitness reduction, weight loss, kyphosis, older appearance, and shorter lifespan than that of WT controls. Elimination of senescent cells from old Prf1-/- mice can be achieved by pharmacological inhibitors of the BCL-2 family of proteins, such as ABT-737. This pharmacological approach attenuates age-related phenotypes and gene expression profile in Prf1-/- mice.


There are more notices here. Transplanting senecent cells to a young body induced inflammation and it seems the immune system doesn't clear them all. Therefore, there is more to the story than simple immune system malfunction or deficiency. On the other hand, it means that senolitics might bring surprisingly good results even in younger individuals, who manged to accumulate a lot be of SC due to some stress ( chemical, oxidative, genetic malfunction, radiation, etc)

Of course, the definition of senecent cells is not a very rigorous one. I would rather focus on the SASP cells. There might be cells that are kinda damaged but inert and mostly harmless, even if not performing to 100 percent of the related tissue normal potential.

On the other hand, there might be cells that secrete pro -inflammatory factors even without being fully damaged. Some of them might be repaired or brought back to the"senses" of normal operation and others might be simpler to kill.

The repair and rehabilitation of the SASP cells might be done by up regulating the repair and autophagy pathways. Calorie restrictions mimetic promises to bring some benefit here. Another approach is intermittent or periodic fasting, combined with autophagy inducing small molecules.
Clearing the remaining senecent cells can be done with senolytics.

OISIN's approach looks very promising and it can be combined with other therapies. Cycling calorie restriction with senolytics can probably increase the Messiah life expectancy by as much as 10 years. We will not be able to do any conclusions on the maximum lifespan for humans, since it would take many decades to gather enough statistics. Unless, a 120-old using senolytics and CR/CR mimetics can love up to 130
. A quick Google search shows the oldest confirmed person alone to be 115 years old, so even if the approach can allow for loving up to 130 years we will not be able to know it for at least another 15 years...

Posted by: Cuberat at December 28th, 2018 7:52 PM

@Cuberat: Good thoughts on transplantation into young animals as an argument against a dominant role for immunosurveillance in senescent cell numbers.

Posted by: Reason at December 29th, 2018 8:05 AM

I had actually forgotten about the work showing implanting senescent cells into young animals caused inflammation; that's actually rather peculiar and really does suggest that there's more going on here than just a decline in immune functionality. It would indeed seem that chronically senescent cells are actively evading immune surveillance, not unlike cancer cells, and they exhibit the further cancer hallmark of being resistant to programmed cell death.

Intuitively, that makes sense, given the documented role of telomere attrition and the DNA damage response in initiating the shift to a senescent phenotype, but I'm not sure @Cuberat's suggestion that the SASP starts developing in pre-senescent cells; the literature I've read on the topic suggests the opposite, that chronically senescent cells gain additional functionally over time.

Considering the traits they share with cancer cells, I would suggest instead that chronically senescent cells originate from precancerous cells that failed to overcome the Hayflick limit.

Posted by: Dylan Mah at December 29th, 2018 8:25 AM

A more productive approach would be to concentrate efforts on thymus rejuvenation.

Posted by: Nathan at December 29th, 2018 9:21 AM

>A more productive approach would be to concentrate efforts on thymus rejuvenation
They are not mutually exclusive. An inefficient thymus might accelerate the senecent cells formation but once formed, they are hard to get rid of. On the other hand, even clearing 100% of the SC might not replace nor compensate for the lost thymus functionality.

Posted by: Cuberat at December 29th, 2018 10:32 AM

@Reason,@Dylan Mah
>I had actually forgotten about the work showing implanting senescent cells into young animals caused inflammation;

The wisdom of crowds and having many pairs of eyes help sometimes...

Posted by: Cuberat at December 29th, 2018 10:35 AM

Jut because the immune system clears out senescent cells doesn't necessarily mean that it does this job perfectly. Many people, including myself, suffer from early onset osteoarthritis in a joint that was injured/broken in their youth playing sport. Senescent cells were probably generated during the healing process in order to signal a stop to re-growth, but not all of the senescent cells were cleared out perfectly by the immune system. If youthful immune systems are perfect at clearing out senescent cells, then there must be some other mechanism for early onset OA in injured joints.

Also it is actually somewhat impressive that senescent cells survive transplantation to younger animals, given that in human trials of mesenchymal stem cells all the cells die sometime after transplant.

Posted by: Jim at December 30th, 2018 2:19 AM

>Also it is actually somewhat impressive that senescent cells survive transplantation to younger animals, given that in human trials of mesenchymal stem cells all the cells die sometime after transplant.

,@Dylan Mah
Considering the traits they share with cancer cells, I would suggest instead that chronically senescent cells originate from precancerous cells ..

If we assume that the senecent cells share the same properties as cancer then there's no surprise that they don't die out when transplanted. On the other hand, when transplanted, it seems, the stem cells actually commit suicide because they don't receive the correct factors and signals . With similar conditions a senecent cell with malfunctioning apoptosis could linger for much longer.

Of course, it's all very speculative. I could imagine another scenario why SC linger. It might be due to their role in wound healing. If I continue my train of thought, we can imagine that successful stem cell transplant might require a percentage of benine senecent stems to serve as anchors. If this is the case, then for a successful stem cell therapy, the senecent cells population can be genetically modified to be vulnerable to a common medication like antibiotics to be used as multiphase approach...

Posted by: Cuberat at December 30th, 2018 9:57 AM

Hi there I'm a composer and write music for healing I'm very interested in your research regarding the reversal of the bad cells in the body zombie cells I lost my father at 60 years old to cancer I know a lot of it had to do with stress and free radicals like taking the train to New York City working at a nuclear power plant he was in great shape exercised but I still believe there can be a reversible effect in these cells I believe it's a combination of the DNA we are supplied with outside variables exercise and eating right obviously is the best But if science can target a specific cell to reverse it's effects and Cancer and other diseases I believe it can happen please keep me posted on the company and its future research on this thank you for your knowledge and your perseverance take care Cathy

Posted by: Catherine sama at February 19th, 2021 10:58 AM
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