Future Directions for the Senescence Field

Today's open access paper is, I think, chiefly interesting for the later section in which the authors ponder future directions for the treatment of aging via means of destroying or manipulating the activity of senescent cells. The accumulation of senescent cells is one of the root causes of aging. The creation of senescent cells happens constantly in the undamaged and fully functional tissues of young people, a tiny fraction of these senescent cells manage to evade destruction and linger to cause issues, and given enough time that fraction will grow large enough to kill you. Cellular senescence isn't the only harmful cause of aging, of course. As things stand, senescent cells speed the death that emerges from other forms of damage, and never have the chance to be the cause of death in and of themselves. Aging is a collaborative murder, carried out via the interaction of many distinct processes.

Selective destruction of senescent cells appears to work well as an approach to remove their contribution to aging. There are comparatively few such cells, no-one has yet found a population of senescent cells that is sufficiently vital to keep around, and numerous methods of destruction either already exist and are under development. By all measures assessed so far, old mice are greatly improved following removal of even a fraction of their senescent cells. To my eyes at least, the path to the future of the senescence field is the very simple one of finding ever more efficient ways to remove these errant and unwanted cells. The first approaches, even as they produce outstanding results in animal studies, are far from perfect. Removing only half of the senescent cell burden leaves half of the job undone, half of the benefits left to be claimed.

Some researchers disagree with the sole focus on destruction, however. They wish to pursue modulation of the bad behavior of senescent cells, or find ways to undo the transition into senescence. I have to think that this is a much harder road to more limited benefits, as well as offering greater risks to patients as damaged cells are pushed into renewed labors. Cellular senescence serves a purpose, in that it is protective against cancer, aids in regeneration from injury, and is a vital part of the replication limit imposed on most cells. In all such cases, the requirement for senescence and its characteristic behaviors is brief and the senescent cells can and should be removed afterwards. If a cell has become senescent due to DNA damage, with the accompanying risk of cancer, then better to remove it than to try to restore it, at least at our present level of technological sophistication.

The senescent cell epigenome

When cellular senescence was first characterized in in vitro cell culture, links to tissue and organismal aging were proposed. Critics of cellular senescence questioned its relevance to in vivo aging, their possibility of being an artefact and the inevitable lack of senescence despite normal aging in lower organisms. Senescence as a pro-aging phenomenon gained popularity with the discovery of biomarkers such as p16 and beta-galactosidase in multiple aged tissues. Mechanistically, the idea of senescent cells being causal in chronic inflammation characteristic of aging, also gained momentum with the discovery of the senescence-associated secretory phenotype (SASP).

The senescence field came of age with four major milestones, (a) two proof-of-concept studies showed major improvement in healthspan and lifespan in mice by the targeted ablation of senescent cells, (b) development of small molecule senolytics as a therapeutic strategy for clearing senescent cells, (c) demonstration that senolytics improve physiological function and lifespan in aged mice and (d) the success of senolytics in pre-clinical studies of a range of age-related conditions. Below, we discuss potential alternatives to senolytics that can deploy epigenetic proteins as "switches" to turn on/off specific pathways in senescent cells for their effective elimination.

SASP inhibitors

Despite the overwhelming success of senolytics, fundamental concerns about specificity and safety prevail. Additionally, the potential benefit of senolytics in treating age-related disease remains to be tested. A second class of molecules that have shown promise in anti-aging rejuvenation therapies is SASP inhibitors. The concept of annihilating the pro-aging arm of senescent cells while preserving the anti-tumor arm is a very attractive treatment option in the elderly who have a high incidence of cancer. Both rapamycin and metformin have shown anti-SASP effects and are on the road to clinical trial for aging. Alternatively, epigenetic enzymes that play a key role in turning on SASP genes (MLL1 and BRD4) can be inhibited by small molecules to prevent its deleterious effects.

Autophagy activation

Autophagy is a self-degenerative process that clears and recycles damaged cellular components. In a seminal publication, it was reported that basal autophagy is essential to maintain the stem-cell quiescent state while preventing senescence of muscle satellite cells in mice. Furthermore, autophagy declines during aging, calorie restriction activates autophagy, and dysfunctional autophagy is evident in Alzheimer's disease pathology. Thus, boosting general macroautophagy (non-selective) is a viable anti-aging avenue. The challenge of autophagy-promoting strategies however comes from observations that autophagy of "nuclear" substrates might in fact contribute to senescence, aging, and inflammation.

Immune-mediated clearance

Senescent cells are naturally cleared by innate immune mechanisms with the macrophage playing a central role. However, immune cells themselves undergo progressive decline in function (termed immunosenescence) that actively contributes to senescent cell accumulation. Furthermore, it has been proposed that subsets of senescent cells become resistant to immune-mediated clearance. Therefore, epigenetic interventions that boost immune surveillance in aged tissues or antibody-based therapies that revert the immune-resistance of senescent cells may also be future rejuvenation strategies.

Rejuvenation therapy

The principles of regenerative medicine can be applied in aging and age-related disease. Expression of pluripotency factors in senescent cells have been shown to allow cell cycle entry with reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism. Additionally, their expression in mice has also shown amelioration of a panel of age-related phenotypes. Epigenetic factors that can potentiate reprogramming can be used to rejuvenate senescent/aged cells. However, it is important to be cautious with regenerative therapy in the elderly because of its potential to be pro-tumorigenic.

Other potential epigenetic therapies

The emerging conceptual themes that arise from the observations are (a) a gradual euchromatinization of the genome, (b) loss or disorganization of constitutive heterochromatin due to (c) breakdown of the nuclear lamina and changes in nuclear morphology and (d) loss of spatial organization of the genome. These large-scale changes manifest in profound transcriptional alterations that ultimately activate programs such as SASP and contribute to transcriptional noise. Systematic screens for epigenetic factors will likely yield potential candidates that can be targeted to prevent or reverse the detrimental effects of senescence.

Comments

Here is a recent paper that explains why one can not just look at the phenomena of senescence as a DNA damage issue, how it is a broader part of the wider tissue plasticity landscape, and why "modulation of the bad behavior of senescent cells" is a legitimate approach in the seno-reversion basket

"Dynamical analysis of cellular ageing by modeling of gene regulatory network based attractor landscape" - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983441/

We've ignored these possibilities in oncology for years to our detriment, and risk the same here as well

"How to escape the cancer attractor: rationale and limitations of multi-target drugs" - https://health.uconn.edu/quantitative-medicine/wp-content/uploads/sites/117/2017/08/Kauffman.pdf

Posted by: Ira S. Pastor at November 20th, 2018 8:45 AM

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