Researchers publishing in Frontiers of Aging Neuroscience Journal have discovered a new way in which senescent cells contribute to aging and chronic disease.
The sympathetic nervous system in age-related diseases
Our nervous systems are divided into the central nervous system, which consists of the brain and spinal cord, and the peripheral nervous system, which is everything else. The peripheral nervous system is divided further into the autonomic and somatic nervous systems. ‘Autonomic’ refers to the aspects we do not consciously control, such as heart rate, while the somatic nervous system controls conscious actions, mostly skeletal muscles. Finally, the autonomic nervous system is split into two opposing systems of nerves: the sympathetic and parasympathetic. Activated sympathetic nerves are best known for their role in the fight-or-flight response. They elevate blood pressure, suppress digestion, and make us start to sweat, among others, while the parasympathetic system does the reverse.
An overactive sympathetic nervous system, perhaps unsurprisingly as a stress response, has been implicated in a number of age-related disorders, especially high blood pressure and cardiovascular disease. A high density of sympathetic nerve fibers (SNFs) has also been found in many tumor types. Suppression of sympathetic nervous activity (most often done with beta blockers, which counteract adrenaline and reduce blood pressure) can have a wide array of unexpected effects, but there have been a limited number of studies.
A collaboration between Hubei University, Peking University, and Hunan Normal University in China has recently investigated the role that senescent cells play in sympathetic nervous system over-activity . They first showed SNF density to increase in two models of aging: in various tissues of naturally aged mice and in human colon adenoma tissues. Senescent cells were found alongside SNFs as evidenced by expression of p16, which suppresses proliferation, and SA β-gal, a marker of cellular senescence.
Propranolol hydrochloride, a beta blocker that inhibits sympathetic nerve activity, was then injected into naturally aged mice. Behavioral tests suggested that cognition was improved in these mice. Additionally, denervation with the neurotoxic drug 6-OHDA reduced the progression of fatty liver disease in a mouse model.
Senescent fibroblasts recruit SNFs via Netrin-1
Hypothesizing that the secreted factors (the SASP) of the senescent cells were recruiting the sympathetic fibers, the researchers conducted an in vitro co-culture of a dorsal root ganglion (an SNF) and fibroblast cells. They induced senescence using three different methods in two different types of fibroblasts. All six combinations recruited SNF outgrowth in greater numbers than their non-senescent counterparts. Subcutaneous implantation of bleomycin-induced senescent fibroblasts in mice also recruited SNFs, while young fibroblasts did not. Next, the researchers surgically induced osteoarthritis in mice and observed an increase in SNFs in these joints. Intra-articular injection of the senolytic drugs dasatinib and quercetin (D+Q) reduced both the senescent cell and SNF burden.
Six secretory factors known to be involved in nerve fiber growth were then investigated. Of them, Netrin-1 was found to increase 10-fold in senescent cells, while no change was found in the other five. Even more convincingly, blocking Netrin-1 activity completely prevented the SNF recruitment seen in the previous experiments both in vitro and in vivo.
In summary, in the present study we found elevated SFs densities in naturally aged mouse tissues and human colon adenoma tissues. Mechanistically, senescent cells-secreted netrin-1 induces the infiltration of SFs, which contributes to elevated SF, increasing their density in aging tissues. The recruited SFs upregulate the SASP profile by releasing the adrenalin transmitter, which acts on senescent cells. Furthermore, the increased SF density impairs brain cognitive performance in naturally aged mice and mediates hepatic steatosis in APOE−/− mice (Figure 8). Our finding suggests that clearing senescent cells or targeting netrin-1 are promising preventive strategies for treating SNS hyperactivity-induced aging-related pathologies.
One of the identified benefits of cellular senescence is in wound healing. In this context, it is not surprising that the SASP would contain recruitment factors in order to encourage nerves to re-enervate the newly formed tissue. It also follows that when this signaling becomes chronic and systemic, as is the case with age-related senescent cell burden, it would contribute to the overactivity of the sympathetic nervous system.
As with most research, we are left with more questions. Do these findings apply to non-fibroblast senescent cells? Can the effects of Netrin-1 be targeted to reduce age-related decline? Importantly, the mechanisms by which SNFs contribute to age-related decline are largely unexplored and may provide insights into how to intervene in these processes with fewer side effects. This study represents an important step in connecting these concepts for the benefit of human health.
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 Yu, A. Q., Wang, J., Zhou, X.J., Chen, K.Y., Cao, Y.D., Wang, Z.X., and Mao, Z.B., (2020). Senescent Cell-Secreted Netrin-1 Modulates Aging-Related Disorders by Recruiting Sympathetic Fibers. Frontiers of Aging Neuroscience, 12:507140. https://doi.org/10.3389/fnagi.2020.507140