Effects of Geroprotective Drugs on Skeletal Health are Largely Unknown

The various geroprotective drugs capable of upregulating cellular maintenance processes in order to modestly slowing aging in short-lived laboratory species are a mixed bunch, ranging from the only technically geroprotective, including well characterized, and well used drugs such as aspirin, to drugs with very mixed data for small effects, such as metformin, through to the better end of the range such as mTOR inhibitors like rapamycin that reliably slow aging. Even in the case of rapamcyin, it remains unclear that the benefits in long-lived species such as our own are all that much better than a good exercise program or the practice of calorie restriction. Senolytic drugs are technically also lumped under the geroprotective heading, but as an actual rejuvenation therapy, and one that produces profoundly greater reversal of age-related diseases in animal models than is the case for other geroprotectives, this has always seemed to me to be a very different class of treatment.

Recent work has shown that it is possible to prevent or even reverse the dysregulation of oxidative stress, autophagy, and the occurrence of senescence using a new class of drugs called geroprotectors. Geroprotectors are drugs that delay or reverse ageing processes and in doing so target the major risk factors for age-related diseases. They promise to promote health span of more than one organ system at the same time in animal models. Studies in model organisms or retrospective studies in patients show that they can ameliorate tissue dysfunction and reduce the onset and severity of many diseases. Over 200 compounds have been classified as geroprotectors, each reported to slow ageing and/or extend lifespan in a variety of organisms.

Such drugs could have distinct advantages over present treatments in osteoporosis (OP) and offer new opportunities for osteoarthritis (OA) due to the fact that they may be able to prevent both OP and OA and their co-morbidities. However, the effects of geroprotectors on skeletal health have received little attention compared to other organ systems with the assumption that these drugs will work equally well for all tissues. Here we review the evidence available to address whether geroprotectors have potential for the care of skeletal age-related diseases and their co-morbidities. We focus on drugs with a good safety profile, which have been shown to target ageing pathways, extend the lifespan and healthspan in animal models and have some evidence of improving health in humans by demonstrating protection from multiple-age-related diseases and for which there are well designed studies in animal models of OP and OA or clinical data available.

Geroprotectors potentially have additional benefits to treat OA and OP and their co-morbidities. However, few studies focus on skeletal health despite their burden of disease. Only one study with the combination of senolytics dasatinib and quercetin shows signs of improvement in a model of bone loss and no improvement has been demonstrated so far in aged models of OA. These studies highlight that extension of lifespan cannot be considered a surrogate marker for extension of health span in all tissues and thorough studies in aged models of OP and OA are required to assess the real benefit of geroprotectors to improve skeletal health.

Link: https://doi.org/10.3389/fcell.2022.682045

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