An overview of what you’ll learn from this blog post:
- What senescent cells are
- Find out how senolytics could remove senescent cells
- Learn how senomorphics may alter senescent cells to become harmless
- How our immune system could be rejuvenated to remove senescent cells
As we age an increasing number of our old cells enter a state known as cellular senescence. These cells no longer divide and instead secrete a cocktail of pro-inflammatory signals known as the senescence-associated secretory phenotype (SASP). Senescent cells and their SASP are thought to be one of the reasons we age.
The SASP can harm tissue regeneration and appears to support the onset and progression of a number of age-related diseases. Worse still, the presence of senescent cells can also cause other nearby healthy cells to become senescent too.
Normally these problem cells are removed by the immune system after they destroy themselves through a process called apoptosis. However, like many things as we age, our immune system starts to wear out and these cells are no longer removed. An increasing amount of cells evade apoptosis resulting in a rising level of chronic inflammation.
Destroying senescent cells with senolytics
One potential solution to this problem is the development of drugs known as senolytics. These senotherapeutic drugs can induce apoptosis (cell death) by targeting the pro-survival pathways senescent cells use to survive allowing them to be removed.
Senolytics were first discovered when researchers removed senescent cells from mice using a transgenic suicide gene therapy that triggered apoptosis. The result of this was that both the health and lifespan of the mice was increased as the presence of senescent cells and their proinflammatory signals were removed. Follow-up studies showed that the same could be achieved using drugs.
A 2016 study showed that senolytics appear to have a positive impact on vascular aging. This was the first study that suggested that senolytics may be useful in the context of cardiovascular diseases. The same year senolytics were used to treat atherosclerosis in mice by targeting foam cells that accumulate and form the basis of arterial plaques. These bloated macrophages have senescence markers and their removal with a senolytic agent lead to significant lesion regression.
Senescent cells are present in many age-related diseases and some research has looked at type 2 diabetes and the potential of senolytics to treat it. There is evidence that SASP from the senescent cells interferes with β-cell function, mediates tissue damage, and promotes adipose tissue dysfunction.
And if that was not bad enough, it seems that the signaling and metabolic changes that accompany diabetes also encourage more cells to become senescent. It could be that senescent cells form a vicious cycle and are both a cause and consequence of harmful metabolic changes and tissue damage. Eliminating senescent cells and the SASP they produce could be a way to break this cycle and restore healthy metabolism.
Another area where senolytics may prove useful is skin aging. The reduction of senescent cells and its SASP may help slow down how fast our skin ages. Although the role of senescent cells in skin is complex because they support wound healing. More research is needed to ascertain if senolytics can delay skin aging.
There has been a great deal of research into senolytics over the last few years and the race is on to successfully demonstrate that senolytics work in humans as they do in animals.
With Unity Biotechnology currently in human trials with senolytics for diabetic macular edema and several other companies hot on their heels, this area of research has truly exploded. While it is hard to predict when senolytics will reach the market due to the nature of human trials, we may see these arrive within the next decade, provided results translate of course.
Silencing senescent cells with senomorphics
Another potential strategy to dealing with senescent cells are senomorphics. These are a class of senotherapeutics related to senolytics that aim to modify the problem cells or SASP secretions rather than directly cause apoptosis.
There have been quite a number of potential senomorphics identified so far including Rapamycin and other mTOR inhibitors, Metformin, Janus Kinase Inhibitors, apigenin, Kaempferol, Loperamide, NDGA, Simvastatin and more.
There has been quite a bit of interest in developing senomorphics in recent years though the approach is currently not as popular as senolytics.
Senolytics vs senolytics
At this time senolytics do appear to be a better option than senomoprhics. This is mainly due to the fact that removing the problem cells completely removes the SASP and the complexity of keeping it in check.
Another plus is that senolytics would likely only need to be used infrequently to keep levels of senescent cells down, the so-called “hit and run” strategy. This is favorable when compared to the need to constantly take a drug to block the SASP.
It should be noted that there is no data for the long-term use of senolytics and it could be a case that using them could be harmful. Little is known about the long-term impact of purging senescent cells especially in the context of very old people who have large numbers of these cells. Fortunately this is what clinical trials are for and we are on the road to finding out.
Boosting immune surveillance
Finally, another option for dealing with senescent cells is to use our own intrinsic “senolytic” system, the immune system. As we age our immune system declines and stops working efficiently, this is called immunosenescence. One consequence of this is the decline of immune surveillance and the clearance of senescent cells from tissues.
But imagine if the immune system could be rebooted and made to work like it did when younger. A rejuvenated immune system would most likely start clearing house properly again leading to the removal of senescent cells. It could potentially make senolytics and senomorphics obsolete if successful.
There are considerable research efforts going into developing immune system boosting and restorative therapies and it has great potential. After all, the immune system is our own personal and adaptable solution to disease. A rejuvenated immune system could have big ramifications for not just age-related diseases, but for a host of other diseases too.
Looking to the future
These therapies, if successful in clinical trials, will likely start to arrive in the next decade or so and all have the potential to be transformative in the context of aging. Next, we will take a look at a technology being developed now that could be a real game changer.