Wednesday, December 29, 2021

Senolytic therapies for healthy longevity

An article on increasing longevity by getting rid of senescent cells (cells that have stopped dividing and generate products that accelerate aging) has been languishing in my queue of potential posts for over a year, and I want to finally give it a mention. (This continues the thread of MindBlog posts over the years that have dealt with anti-aging supplements. You can enter 'resveratrol' in the search box in the right column of this blog to get a sample. I've reported on several self experiments, none of which ended all that well. A 2008 post on my experimenting with a resveratrol supplement generated a comment thread that has continued for many years.)

Here is the abstract of the review article by Jan M. van Deursen in Science Magazine:

The estimated “natural” life span of humans is ∼30 years, but improvements in working conditions, housing, sanitation, and medicine have extended this to ∼80 years in most developed countries. However, much of the population now experiences aging-associated tissue deterioration. Healthy aging is limited by a lack of natural selection, which favors genetic programs that confer fitness early in life to maximize reproductive output. There is no selection for whether these alterations have detrimental effects later in life. One such program is cellular senescence, whereby cells become unable to divide. Cellular senescence enhances reproductive success by blocking cancer cell proliferation, but it decreases the health of the old by littering tissues with dysfunctional senescent cells (SNCs). In mice, the selective elimination of SNCs (senolysis) extends median life span and prevents or attenuates age-associated diseases (1, 2). This has inspired the development of targeted senolytic drugs to eliminate the SNCs that drive age-associated disease in humans.
A few clips from the article:
Much of our current knowledge about the properties of SNCs is based on experiments in cultured cells, largely because SNCs in tissues and organs are difficult to identify and collect. One key characteristic of SNCs is that they are in a state of permanent cell-cycle arrest....SNCs produce a bioactive “secretome,” referred to as the senescence-associated secretory phenotype (SASP). This can disrupt normal tissue architecture and function through diverse mechanisms, including recruitment of inflammatory immune cells, remodeling of the extracellular matrix, induction of fibrosis, and inhibition of stem cell function . Paradoxically, although cellular senescence has evolved as a tumor protective program, the SASP can include factors that stimulate neoplastic cell growth, tumor angiogenesis, and metastasis, thereby promoting the development of late-life cancers. Indeed, elimination of SNCs with aging attenuates tumor formation in mice, raising the possibility that senolysis might be an effective strategy to treat cancer.
The article proceeds to outline several different efforts to identify senolytic drug targets. It notes that:
...natural products with anticancer properties, such as quercetin and fisetin, and quercetin in combination with the pan-tyrosine kinase inhibitor dasatinib, have been reported to eliminate SNCs in vitro and in mice [M. Xu et al., Nat. Med. 24, 1246 (2018); M. J. Yousefzadeh et al., EBioMedicine 36, 18 (2018)]. Although quercetin, fisetin, and dasatinib are often referred to as senolytics, it should be noted that they each act on a myriad of pathways and mechanisms implicated in diverse biological processes. This makes it difficult to decipher how these drugs eliminate or otherwise impact SNCs and to attribute any therapeutic or detrimental effects they may have in clinical trials to senolysis.
A brief google search on these flavinoid antioxidant compounds (found in fruits and vegetables...strawberries, watercress, cilantro, etc.) finds a large number of "Life Extension" dietary supplements featuring them. There is no data on their effects on senolysis or life span in humans.


  1. Seems appropriate that you wrote 'anguishing in your queue' when presumably you meant languishing.

  2. Oppps! Quite a Freudian slip. I did correct it, though you are right that it does seem appropriate.