What can we do about cellular senescence?

The accumulation of senescent cells in our bodies causes a lot of problems, but they also serve an important function. Recent findings have shed more light on this phenomena and how we might resolve the issues surrounding it.

Senescent cells are also known as ‘zombie cells’. They cease to divide and replicate, harm tissue around them and never dies.

Cellular senescence are one of the more studied factors contributing to aging. Before I go into why the accumulation of these cells are bad for us, it is important to note that they may have an important function that has evolved in our bodies.

Senescent cells are in a permanent cell cycle arrest which may occur when the ends of its chromosomes reach a critical length, as was elaborated upon in the previous post. However, there is evidence for this being a mechanism to prevent tumors from developing. Tumors can form from all cell types except those who have been terminally differentiated, and they can proliferate unchecked by hijacking our regenerative capabilities. Cells have genes coding for proteins that regulates its cell cycle, ensuring that it divides when necessary and that it stops when it is not needed. If the genetic information coding for these proteins are damaged, mutated or lost, the cell may divide uncontrollably, resulting tumorigenesis. The key player in all of this is called the ‘Guardian of the Genome’, namely the protein p53. When a cell is stressed from either exogenous or endogenous factors, it will sound the alarm and send signals to its composite parts, which may trigger an increase in the expression of p53 in an attempt to resolve the issue. p53 expression either enables or inhibits certain enzymes from catalyzing, depending on which signals are emitted. It can enable cell death or DNA repair, or it can inhibit cell growth which may become permanent — leading to senescence.

Senescent cells differ in their morphology when compared to young healthy cells. Senescent cells are identified by this change in morphology (e.g. an enlarged nucleus) and activity (e.g. secretion of inflammatory cytokines), causing inflammation to its neighboring cells and surrounding tissue, ultimately leading to dysfunction.
SOURCE: https://doi.org/10.1016/j.redox.2016.12.001

Paradoxically, although senescent cells are in a permanent cell cycle arrest to prevent tumors from growing, they secrete harmful molecules to their healthy neighboring cells and surrounding tissue, which may stimulate tumor progression. This is due to their senescence-associated secretory phenotype (SASP), causing senescent cells to secrete inflammatory cytokines, interleukins and growth factors.

As such, it seems the most prudent approaches are to either prevent senescent cells from accumulating, or to remove them all together with a viral technique sophisticated enough to discern them from healthy cells. Remarkably, in 2016, a study demonstrated that injecting mice intraperitoneally with a liposomal formulation of clodronate, removed ~80% of all their senescent cells while causing almost no harm to healthy cells. Old mice became rejuvenated and even regrew lost hair.

Assay illustrating cell viability of incubated senescent cells (Sen) and control IMR90 with increasing doses of FOXO4-DRI
Selectivity index (SI50) reflects differences in EC50 of a non-regression analysis for both groups.
SOURCE: https://doi.org/10.1016/j.cell.2017.02.031

Furthermore, in 2017, another study identified another angle of attack for targeting senescent cells, and in doing so elucidated why senescent cells don’t die but rather accumulates in our bodies. Evidently, this is due to a protein-protein interaction (FOXO4-p53) repressing their apoptotic response. As a result, they designed a peptide (FOXO4-DRI) to perturb this interaction resulting in induced targeted apoptosis of senescent cells. Their experiments using this designed peptide, showed a marked reduction in cell viability for their incubated senescent cells compared to their controls (~12-fold difference). These striking findings have encouraged new companies to look at treatments targeting senescent cells to combat age-related diseases and even aging itself, and human trials have already begun.

Picture of two mice, both the same age. One treated with the clodronate compound injection, the other one untreated. Which one do you think received the treatment?
SOURCE: doi: 10.1038/nature16932

In the previous post, I went into detail about the evidence demonstrating significant health benefits from elevated levels in NAD+ in our cells. Consolidating NAD+ supplementation with this technique — injecting compounds to kill off senescent cells — is just the beginning. Different teams of researchers attacking aging from different angles and perspectives, have delivered incredible new insight into the aging process and how we can prevent it. These recent findings will lay the groundwork radical new therapies and it may initiate a cascade of new discoveries to come.

These two microscope pictures of kidney cells from one of the companies looking at treatments against senescent cells, illustrate how treatments can remove a substantial amount of them. Notice the difference in senescent cell density (coloured blue) between pre-treatment (A) and post-treatment (B)

SOURCE: Oisín Biotechnologies, Inc.



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