A group of researchers has found that early long-term treatment of mice with the popular senolytic duo dasatinib and quercetin alleviates symptoms of intervertebral disc degeneration, a major age-related cause of disability [1].
Age-related disease with early onset
Conventional wisdom says that our spines just were not built to last for as long as humans live today, especially considering how many of us lead sedentary lives. In most people, the constant strain causes the development of spinal abnormalities quite early in life. Intervertebral discs, which give the spine its flexibility and the ability to absorb shocks, are especially vulnerable. They degenerate faster than other musculoskeletal tissues, with the first signs usually appearing in our early teens [2].
One study found that the prevalence of intervertebral disc degeneration over the entire spine was 71% in men and 77% in women aged less than 50 years and more than 90% in both men and women aged more than 50 years [3]. Intervertebral disc degeneration is the leading cause of low back pain, which, in turn, is a major cause of age-related disability.
Intervertebral discs and senescence
Intervertebral discs consist of dense fluid, rich in the protein aggrecan, packed into an even denser flexible envelope made mainly of collagen fibers. Disc degeneration is caused by the degradation of its extracellular matrix (ECM) along with increased inflammation and cellular death. These factors alter the discs’ mechanistic properties and hamper their ability to withstand loads.
Why we Age: Cellular Senescence
As your body ages, more of your cells become senescent. Senescent cells do not divide or support the tissues of which they are part; instead, they emit potentially harmful chemical signals, collectively known as the senescence-associated secretory phenotype (SASP), which encourages nearby cells to enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related ...
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Several studies have linked intervertebral disc degeneration to cellular senescence, so it was only natural for scientists to turn their attention to senolytics. Previous research showed promising results, but this time, the scientists decided to investigate the effects of long-term treatment.
They chose the increasingly popular senolytic cocktail of dasatinib and quercetin, commonly known as D + Q. The researchers used healthy mice, dividing them into three groups by the ages when the rodents began receiving regular doses of D + Q: 6, 14, and 18 months. The experiment stopped at 23 months, a respectable old age for mice.
Mice are also prone to intervertebral disc degeneration, so the animals naturally developed such symptoms with age. The study showed that the D + Q cocktail decreased cellular senescence and age-related inflammation, helped preserve healthy ECM, limited aggrecan degradation, reduced fibrosis, and preserved cellular phenotype in the nucleus pulpous (disc fluid).
Not too early, not too late
The results differed across the groups. The most pronounced effects were observed in mice that began receiving their D + Q at the age of 14 months, more or less in parallel with the onset of the symptoms. The group that began receiving the treatment earlier in life, at the age of 6 months, benefited from it somewhat less, while in the third group, treated since the age of 18 months, the positive effects of the drug cocktail were practically indiscernible.
The treatment was well-tolerated by all mice, but it did not result in any meaningful increase in the animals’ life expectancy. It did, however, lead to some increase in grip strength compared to control groups, which might indicate a positive effect on healthspan (less frailty).
No effect on the knees
In addition to intravertebral disc degeneration, the researchers analyzed the effects of the treatment on another, closely related, disorder: osteoarthritis in knee joints. Unfortunately, no difference between the knee joints of treated and untreated mice was found, including in levels of senescence markers. It seems that D + Q, at least in this regimen, fails to alleviate age-related osteoarthritis. Additionally, no positive change was observed between the study groups and the controls in several other parameters, such as bone density.
The scientists conclude that long-term D + Q treatment “shows differential effects on progression of aging pathologies depending on the skeletal tissue type (i.e., disc, bone, or cartilage) and starting point of treatment”. The most important takeaway from the study, according to its authors, is that there seems to be a therapeutic window for senolytic intervention in age-related intervertebral disc degeneration, and that, if administered during this window, the D + Q cocktail might be able to produce meaningful improvements.
Conclusion
Following previous research that showed the link between cellular senescence and intervertebral disc degeneration, this new study demonstrates that senolytic drugs have the potential to treat this disorder if the treatment begins soon after the early signs of disc degeneration appear. It does not mean, however, that hope is lost for humans with more advanced symptoms (including yours truly). This is a limited-scale study that paves the way for more serious research that might yield better results.
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Literature
[1] Novais, E. J., Tran, V. A., Johnston, S. N., Darris, K. R., Roupas, A. J., Sessions, G. A., … & Risbud, M. V. (2021). Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice. Nature Communications, 12(1), 1-17.
[2] Urban, J. P., & Roberts, S. (2003). Degeneration of the intervertebral disc. Arthritis Res Ther, 5(3), 1-11.
[3] Teraguchi, M., Yoshimura, N., Hashizume, H., Muraki, S., Yamada, H., Minamide, A., … & Yoshida, M. (2014). Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study. Osteoarthritis and cartilage, 22(1), 104-110.
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