An Overview of the Present State of Development of Senotherapeutics

Senotherapeutics are treatments that in some way reduce the burden of senescent cell accumulation in old tissues. This is a broader category than senolytics, therapies that destroy senescent cells, and includes efforts to modulate the harmful signaling of senescent cells without destroying them. I'd say that latter strategy has little to recommend it at the present time; one would need evidence for significant vital populations of senescent cells in the brain to start to think about modulation rather than destruction. So far the approach of targeted destruction is doing very well in mouse studies, robustly producing rejuvenation and extension of healthy life span, even using therapeutics that are far from optimal in comparison to the improved versions now under development.

This paper is not open access, but in a world in which the copyright heretics of Sci-Hub continue to endure, journal paywalls now present little hindrance for the curious. I point it out because in addition to the initial overview of the biochemistry of cellular senescence in the context of aging, it also contains well presented tables of current senotherapeutics, their evidence, and their progress towards the clinic. This is a useful resource for those thinking seriously about self-experimentation or putting together pilot clinical trials.

Accumulating evidence suggests that, in contrast to the cell-autonomous tumor-suppressive mechanism of senescence, the paracrine effects of senescent cells themselves, particularly those mediated by the senescence-associated secretory phenotype (SASP), are responsible for aging-related pathologies, among which cancer has attracted increasing attention. Optimizing the beneficial impact while minimizing the deleterious effects of cellular senescence remains a serious challenge for multiple fields of scientific and clinical research.

Transient induction of cellular senescence, followed by tissue remodeling and senescent cell elimination by the immune system, is beneficial because it facilitates removal of damaged cells from the affected tissue. However, chronic senescence or inability to eliminate the senescent cells is frequently observed in aged individuals or in pathological contexts, leading to the accumulation of senescent cells which produce adverse effects.

Increasing evidence shows that both pro-senescence and anti-senescence therapies can be beneficial to tissue homeostasis. For instance, in the case of cancer, pro-senescence therapies can minimize the damage by limiting aberrant activities such as hyperactive proliferation, and more specifically by preventing or delaying events of carcinogenesis, while anti-senescence treatments may help to remove accumulated senescent cells and allow tissue regeneration. Of note, the term "anti-senescence" in this field of research does not mean that senescence is blocked or prevented, but means that when senescence is engaged it is subsequently pushed into apoptosis.

A two-step anticancer strategy was recently suggested in which senescence-inducing treatments are followed by senotherapy, thus providing a novel option to maximize therapeutic efficacy and improve clinical outcome. Although the incidence of senescence can improve long-term outcomes for cancer, the potentially harmful properties of senescent cells persisting in vivo make their quantitative elimination an outstanding therapeutic priority.

The most promising senolytics appear to be inhibitors of pro-survival BCL family proteins, probably because senescent cells physiologically need these factors to circumvent apoptosis for long-term survival. This class of agents has undergone extensive investigation in patients with chronic leukemia, with final FDA approval of a selective BCL-2 inhibitor, venetoclax. However, venetoclax is not a potent senolytic agent in vitro, whereas its homolog navitoclax has recently been disclosed to be one of the strongest senolytics. Navitoclax effectively inhibits BCL-2, BCL-xL, and BCL-W, suggesting that senolysis requires suppression of a wider range of anti-apoptotic effectors than of BCL-2 alone. It is rational to propose a broad spectrum of BCL protein inhibitors as a potential senolysis treatment in patients, but such molecules would need to exhibit acceptable toxicity through new or optimized formulation, delivery, or administration schedule.

Link: https://doi.org/10.1016/j.molmed.2018.08.002

Comments

>efforts to modulate the harmful signaling of senescent cells without destroying them. I'd say that latter strategy has little to recommend it at the present...

There are a couple of scenarios I can imagine where modulation would be useful. One is when the cells are given chance to repair themselves. The other is when killing to many senecent cells can lead to adverse immune reactions. Probably the correct approach would be to cycle senolitics with seno-modulation and, pribavly, other antioxidants...

Navitoclax is too new and to expensive, even compared to dasatinib. I guess they both could be combined to get enhanced effects. Too bad I cannot find any such study...

Btw, do we have any updates on Oisin's experiment?. Of has been almost through minus from the publication date...

Posted by: Cuberat at September 5th, 2018 8:24 AM

@Cuberat
Your comments are interesting, but I sometimes find them quite difficult to understand as there appear to be typos and erroneous word substitutions (autocorrect? voice-to-text?).

Posted by: CD at September 5th, 2018 11:10 AM

@CD, and to everybody who tried to read my posts.
My comments might appear profound while they are just obscure and unreadable. Joking aside, it is the autocorrect and posting from a mobile phone, where I see half a screen- full keyboard, which , apparently often has different opinion than me, and 2-3 words of the text I am typing. So, while my gaze is focuses on the keyboard, the previous words get transformed. Sometimes, the textbox gets full and I don't see the text i am typing at all a. At that moment I see only the keyboard. And very often I get lazy and don't proofread...

Posted by: Cuberat at September 5th, 2018 12:07 PM

My speculation is that the first senolytic to be marketed will be a topically applied cream to reverse skin aging. A web search indicates that there is some interest in cosmetic applications. Obviously, this would be a huge market, and probably, would face fewer regulatory barriers.

Posted by: Lou Pagnucco at September 5th, 2018 1:44 PM

It is probably an important area to be developed in tangent, in case senolytics don't pan out

Many of the products in existing senolytic mechanistic categories (TK, BCL-2, MDM2) exhibit various degrees of QTc prolongation - some significant, some not so much

However, if senolytics demonstrate such a safety window issue as they get further into the clinic, their approval could be hindered and their end user market may become limited to more targeted indications that avoid systemic application

Posted by: DrugDev U.S. at September 5th, 2018 3:03 PM

@Cuberat
:)

~
@DrugDev
Good to know about the QTc prolongation.

Posted by: CD at September 6th, 2018 11:12 AM

" ...journal paywalls now present little hindrance for the curious."

If they don't mind leaving themselves open to malicious prosecution or being made an example.

In the US, most have access to interlibrary loan services, even members of the general public can receive ILL services though their local public libraries. Transactions are often all electronic and turnaround times can be a matter of days.

A better long term solution is of course to get researchers to publish in journals that are open access or at least in ones that don't engaging price gouging.

Posted by: CD at September 6th, 2018 1:08 PM

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