Senescent cells accumulate with age. They are never a very sizable proportion of all cells in a tissue, but they causes a great deal of harm via their inflammatory signaling, changing the behavior of surrounding cells for the worse, and contributing to chronic inflammation throughout the body. All of the common age-related diseases appear to be driven by the presence of senescent cells to a significant degree. Over the past decade, a great deal of progress has been made in learning more about the role of cellular senescence in aging, thanks to the development of senolytic therapies capable of selectively destroying these senescent cells.
A number of human trials have been conducted or are underway for the first generation senolytic treatment of dasatinib and quercetin in combination, with promising results so far. Quercetin is a readily available supplement, and dasatinib can in principle be prescribed off label by any physician, so obtaining more human data is an important goal in order to enable widespread use in the populations that may benefit. Unfortunately, since dasatinib is an existing approved drug, there is little incentive for the pharmaceutical industry to underwrite the sizable cost of running the necessary trials. The small number of trials that have been conducted to date arise from academic research. There is an opportunity here for philanthropists to advance the field and the state of knowledge by running informal trials at a lower cost.
Meanwhile, data trickles in slowly from the academic trials. Today's paper describes an interesting result, in that senolytic treatment increases circulating α-klotho in mice and humans, implicating senescent cells in the age-related decline in α-klotho levels. The klotho gene is one of the few robustly establishing longevity genes: in mice, more klotho means a longer life, less klotho means accelerated aging. Klotho levels in humans correlate with longevity and better later life health. The evidence to date suggests that klotho likely acts primarily via improved kidney function. Any decline in kidney function has detrimental effects throughout the body.
α-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential. However, readily clinically-translatable, practical strategies for increasing α-Klotho are not at hand. Here, we report that orally-active, clinically-translatable senolytics can increase α-Klotho in mice and humans.
We examined α-Klotho expression in three different human primary cell types co-cultured with conditioned medium (CM) from senescent or non-senescent cells with or without neutralizing antibodies. We assessed α-Klotho expression in aged, obese, and senescent cell-transplanted mice treated with senolytics. We assayed urinary α-Klotho in patients with idiopathic pulmonary fibrosis (IPF) who were treated with the senolytic drug combination, Dasatinib plus Quercetin (D+Q).
We found exposure to the senescent cell secretome reduces α-Klotho in multiple nonsenescent human cell types. This was partially prevented by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors activin A and Interleukin 1α (IL-1α). Consistent with senescent cells' being a cause of decreased α-Klotho, transplanting senescent cells into younger mice reduced brain and urine α-Klotho. Selectively removing senescent cells genetically or pharmacologically increased α-Klotho in urine, kidney, and brain of mice with increased senescent cell burden, including naturally-aged, diet-induced obese (DIO), or senescent cell-transplanted mice. D+Q increased α-Klotho in urine of patients with IPF, a disease linked to cellular senescence.
In summary, senescent cells cause reduced α-Klotho, partially due to their production of activin A and IL-1α. Targeting senescent cells boosts α-Klotho in mice and humans. Thus, clearing senescent cells restores α-Klotho, potentially opening a novel, translationally-feasible avenue for developing orally-active small molecule, α-Klotho-enhancing clinical interventions. Furthermore, urinary α-Klotho may prove to be a useful test for following treatments in senolytic clinical trials.