Life stress can shorten lifespan and increase risk for aging-related diseases, but the biology underlying this phenomenon remains unclear. Here we assessed the effect of chronic stress on cellular senescence—a hallmark of aging. Exposure to restraint stress, a psychological non-social stress model, increased p21Cip1 exclusively in the brains of male, but not female mice, and in a p16Ink4a-independent manner. Conversely, exposure to chronic subordination stress (only males were tested) increased key senescent cell markers in peripheral blood mononuclear cells, adipose tissue and brain, in a p16Ink4a-dependent manner. p16Ink4a-positive cells in the brain of chronic subordination stress-exposed mice were primarily hippocampal and cortical neurons with evidence of DNA damage that could be reduced by p16Ink4a cell clearance. Clearance of p16Ink4a-positive cells was not sufficient to ameliorate the adverse effects of social stress on measured metrics of healthspan. Overall, our findings indicate that social stress induces an organ-specific and p16Ink4a-dependent accumulation of senescent cells, illuminating a fundamental way by which the social environment can contribute to aging. Exploring the molecular consequences of exposing mice to social stress, Lyons et al. identify that hippocampal and cortical neurons acquire features of senescence, identifying a mechanism through which the social environment may contribute to aging.

OBJECTIVE:Despite advances toward understanding the etiology of Alzheimer's disease (AD), it remains unclear which aspects of this disease are affected by environmental factors. Chronic life stress increases the risk of aging-related diseases including AD. The impact of stress on tauopathies remains understudied. We examined the effects of stress elicited by social (chronic subordination stress [CSS]) or psychological/physical (chronic restraint stress [CRS]) factors on the PS19 mouse model of tauopathy. METHODS:Male PS19 mice (average age, 6.3 months) were randomized to receive CSS or CRS, or to remain as singly housed controls. Behavioral tests were used to assess anxiety-like behaviors and cognitive functions. Immunofluorescence staining and Western blotting analysis were used to measure levels of astrogliosis, microgliosis, and tau burden. Immunohistochemistry was used to assess glucocorticoid receptor expression. RESULTS:PS19 mice exhibit neuroinflammation (glial fibrillary acidic protein, t tests: p = .0297; allograft inflammatory factor 1, t tests: p = .006) and tau hyperphosphorylation ( t test, p = .0446) in the hippocampus, reduced anxiety (post hoc, p = .046), and cognitive deficits, when compared with wild-type mice. Surprisingly, CRS reduced hippocampal levels of both total tau and phospho-tau S404 ( t test, p = .0116), and attenuated some aspects of both astrogliosis and microgliosis in PS19 mice ( t tests, p = .068-.0003); however, this was not associated with significant changes in neurodegeneration or cognitive function. Anxiety-like behaviors were increased by CRS (post hoc, p = .046). Conversely, CSS impaired spatial learning in Barnes maze without impacting tau phosphorylation or neurodegeneration and having a minimal impact on gliosis. CONCLUSIONS:Our results demonstrate that social or psychological stress can differentially impact anxiety-like behavior, select cognitive functions, and some aspects of tau-dependent pathology in PS19 male mice, providing entry points for the development of experimental approaches designed to slow AD progression.

Chronic stress is a risk factor for numerous aging-related diseases and has been shown to shorten lifespan in humans and other social mammals. Yet how life stress causes such a vast range of diseases is still largely unclear. In recent years, the impact of stress on health and aging has been increasingly associated with the dysregulation of the so-called hallmarks of aging. These are basic biological mechanisms that influence intrinsic cellular functions and whose alteration can lead to accelerated aging. Here, we review correlational and experimental literature (primarily focusing on evidence from humans and murine models) on the contribution of life stress - particularly stress derived from adverse social environments - to trigger hallmarks of aging, including cellular senescence, sterile inflammation, telomere shortening, production of reactive oxygen species, DNA damage, and epigenetic changes. We also evaluate the validity of stress-induced senescence and accelerated aging as an etiopathological proposition. Finally, we highlight current gaps of knowledge and future directions for the field, and discuss perspectives for translational geroscience.

Tear gases, or chemical demonstration control agents (DCA), were originally created as weapons that could severely disable or kill enemy troops. Though banned in war, these chemicals are still used in domestic policing. Here we review the available scientific literature on tear gas, summarizing findings from animal and environmental studies as well describing data from new human studies. We find a lack of scientific evidence supporting the safety of tear gas, especially regarding its long-term impacts on human health and the environment. Many of the available studies were published decades ago, and do not parse data by variables such as chemical type and exposure time, nor do they account for the diversity of individuals who are exposed to tear gas in real-life situations. Due to the dearth of scientific research and the misinterpretation of some of the available studies, we conclude that a serious reevaluation of chemical DCA safety and more comprehensive exposure follow-up studies are necessary.

While the U.N. Chemical Weapons Convention bans tear gas and other chemical weapons from use in war, their use is still allowed in domestic policing. Public concern about tear gas utilization increases when social justice protesters are subjected to these chemical demonstration control agents. The history of tear gas utilization by law enforcement in the U.S. is rife with corruption and racist intent. Furthermore, the scientific evidence supporting the safety of tear gas is lacking due to both the misinterpretation of public health studies and the paucity of controlled experiments. We find that the current utilization of tear gas is a threat to public health, free speech, and possibly falls outside of the exception for domestic use. We discuss policy alternatives that include alternative crowd control methods, changes to protocols for tear gas deployment and post-use review, increased regulatory oversight, and the possibility of a complete tear gas ban.

Late onset, sporadic Alzheimer's disease (AD) accounts for the vast majority of cases. Unlike familial AD, the factors that drive the onset of sporadic AD are poorly understood, although aging and stress play a role. The early onset/severity of neuropathology observed in most genetic mouse models of AD hampers the study of the role of aging and environmental factors; thus alternate strategies are necessary to understand the contributions of these factors to sporadic AD. We demonstrate that mice acquiring a low social status (subordinate) in a lifelong chronic psychosocial stress (CPS) model, accrue widespread proteomic changes in the frontal/temporal cortex during aging. To better understand the significance of these stress-induced changes, we compared the differentially expressed proteins (DEPs) of subordinate mice to those of patients at varying stages of dementia. Sixteen and fifteen DEPs upregulated in subordinate mice were also upregulated in patients with mild cognitive impairment (MCI) and AD, respectively. Six of those upregulated proteins (CPE, ERC2, GRIN2B, SLC6A1, SYN1, WFS1) were shared by subordinate mice and patients with MCI or AD. Finally, comparison with a spatially detailed transcriptomic database revealed that the superior frontal gyrus and hippocampus had the greatest overlap between mice subjected to lifelong CPS and AD patients. Overall, most of the overlapping proteins were functionally associated with enhanced NMDA receptor mediated glutamatergic signaling, an excitotoxicity mechanism known to affect neurodegeneration. These findings support the association between stress and AD progression and provide valuable insight into potential early biomarkers and protein mediators of this relationship.

Chronic stress has been shown to promote numerous aging-related diseases, and to accelerate the aging process itself. Of particular interest is the impact of stress on Alzheimer's disease (AD), the most prevalent form of dementia. The vast majority of AD cases have no known genetic cause, making it vital to identify the environmental factors involved in the onset and progression of the disease. Age is the greatest risk factor for AD, and measures of biological aging such as shorter telomere length, significantly increase likelihood for developing AD. Stress is also considered a crucial contributor to AD, as indicated by a formidable body of research, although the mechanisms underlying this association remain unclear. Here we review human and animal literature on the impact of stress on AD and discuss the mechanisms implicated in the interaction. In particular we will focus on the burgeoning body of research demonstrating that senescent cells, which accumulate with age and actively drive a number of aging-related diseases, may be a key mechanism through which stress drives AD.

The brown adipose tissue (BAT) is a thermogenic organ that plays a major role in energy balance, obesity, and diabetes due to the potent glucose and lipid clearance that fuels its thermogenesis, which is largely mediated via sympathetic nervous system activation. However, thus far there has been little experimental validation of the hypothesis that selective neuromodulation of the sympathetic nerves innervating the BAT is sufficient to elicit thermogenesis in mice. We generated mice expressing blue light-activated channelrhodopsin-2 (ChR2) in the sympathetic nerves innervating the BAT using two different strategies: injecting the BAT of C57Bl/6J mice with AAV6-hSyn-ChR2 (H134R)-EYFP; crossbreeding tyrosine hydroxylase-Cre mice with floxed-stop ChR2-EYFP mice. The nerves in the BAT expressing ChR2 were selectively stimulated with a blue LED light positioned underneath the fat pad of anesthetized mice, while the BAT and core temperatures were simultaneously recorded. Using immunohistochemistry we confirmed the selective expression of EYFP in TH positive nerves fibers. In addition, local optogenetic stimulation of the sympathetic nerves induced significant increase in the BAT temperature followed by an increase in core temperature in mice expressing ChR2, but not in the respective controls. The BAT activation was also paralleled by increased levels of pre-UCP1 transcript. Our results demonstrate that local optogenetic stimulation of the sympathetic nerves is sufficient to elicit BAT and core thermogenesis, thus suggesting that peripheral neuromodulation has the potential to be exploited as an alternative to pharmacotherapies to elicit organ activation and thus ameliorate type 2 diabetes and/or obesity.

Significant loss produces the highest degree of stress and compromised well-being in humans. Current rodent models of stress involve the application of physically or psychologically aversive stimuli, but do not address the concept of loss. We developed a rodent model for significant loss, involving removal of long-term access to a rewarding enriched environment. Our results indicate that removal from environmental enrichment produces a profound behavioral and physiological phenotype with depression-like qualities, including helplessness behavior, hypothalamo-pituitary-adrenocortical axis dysregulation and overeating. Importantly, this enrichment removal phenotype was prevented by antidepressant treatment. Furthermore, the effects of enrichment removal do not occur following relief from chronic stress and are not duplicated by loss of exercise or social contact.