Senescent Cells: Emerging Targets for Human Aging and Age-Related Diseases

Song, Shuling; Lam, Eric; Tchkonia, Tamara; Kirkland, James L.; Sun, Yu

doi:10.1016/j.tibs.2020.03.008

Cited by 140 publications

(132 citation statements)

References 135 publications

(169 reference statements)

Supporting

Mentioning

125

Contrasting

Order By: Relevance

“…Other immunomodulator agents such as metformin, imiquimod ( 174 ) and anti-inflammatory drugs inhibiting COX2 expression ( 175 ) (e.g., aspirin and NSAIDS) that are currently approved for clinical use in other settings may represent attractive approaches to promote more effective vaccine responses by transiently alleviating chronic inflammation prior to vaccination. Finally, it is likely that targeting other sources of inflammaging by changing the composition of the microbiome ( 176 ) or selectively removing senescent cells using senolytic drugs ( 177 ) may represent further opportunities for enhancing vaccine immunity in the setting of chronic inflammation.…”

Section: Novel Strategies For Enhancing Vaccine Responsesmentioning

confidence: 99%

Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly

2020

View full text Add to dashboard Cite

One of the most appreciated consequences of immunosenescence is an impaired response to vaccines with advanced age. While most studies report impaired antibody responses in older adults as a correlate of vaccine efficacy, it is now widely appreciated that this may fail to identify important changes occurring in the immune system with age that may affect vaccine efficacy. The impact of immunosenescence on vaccination goes beyond the defects on antibody responses as T cell-mediated responses are reshaped during aging and certainly affect vaccination. Likewise, age-related changes in the innate immune system may have important consequences on antigen presentation and priming of adaptive immune responses. Importantly, a low-level chronic inflammatory status known as inflammaging has been shown to inhibit immune responses to vaccination and pharmacological strategies aiming at blocking baseline inflammation can be potentially used to boost vaccine responses. Yet current strategies aiming at improving immunogenicity in the elderly have mainly focused on the use of adjuvants to promote local inflammation. More research is needed to understand the role of inflammation in vaccine responses and to reconcile these seemingly paradoxical observations. Alternative approaches to improve vaccine responses in the elderly include the use of higher vaccine doses or alternative routes of vaccination showing only limited benefits. This review will explore novel targets and potential new strategies for enhancing vaccine responses in older adults, including the use of anti-inflammatory drugs and immunomodulators.

show abstract

Section: Novel Strategies For Enhancing Vaccine Responsesmentioning

confidence: 99%

Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly

2020

View full text Add to dashboard Cite

show abstract

“…Senescent cells have up-regulated pro-survival pathways, which protect them from their own pro-apoptotic SASP [ 116 , 117 ]. Because they are resistant to apoptosis, senescent cells perpetuate inflammation-related cell dysfunction and SASP [ 47 ].…”

Section: Cellular Senescence and Suppression Of Hsr In Chronic-degenementioning

confidence: 99%

“…Recently, a class of drugs that preferentially target senescent cells (“senolytics”) have entered clinical trials. Senolytics selectively eliminate senescent cells by inducing apoptosis [ 113 , 117 ] and aiming to stop the noxious ER stress-SASP-inflammation vicious cycle and re-establishing the physiological resolution of inflammation via HSR. While senescent cells can be dysfunctional and decrease the survival even in young mice, senolytics can enhance the lifespan in old mice [ 118 ].…”

Section: Bypassing Chronic Suppression Of Hsr and Re-arming The Resolmentioning

confidence: 99%

“…On the other hand, whole body heat treatment or just the maintenance of core temperature at fever-range levels are also feasible and involves physiological antisenescent HSR-inducing strategies. These approaches can be carried out even in an ICU setting and in critical patients, having the advantage of not interfering in immunoinflammatory balance, as is the case of antibodies against particular pro-inflammatory components [ 117 ]. Actually, heat shock inhibits both NLRP3 inflammasome activation and caspase-1 activity in mouse macrophages [ 143 ].…”

Section: Bypassing Chronic Suppression Of Hsr and Re-arming The Resolmentioning

confidence: 99%

See 1 more Smart Citation

Suppressed anti-inflammatory heat shock response in high-risk COVID-19 patients: lessons from basic research (inclusive bats), light on conceivable therapies

et al. 2020

View full text Add to dashboard Cite

The major risk factors to fatal outcome in COVID-19 patients, i.e., elderliness and pre-existing metabolic and cardiovascular diseases (CVD), share in common the characteristic of being chronic degenerative diseases of inflammatory nature associated with defective heat shock response (HSR). The molecular components of the HSR, the principal metabolic pathway leading to the physiological resolution of inflammation, is an anti-inflammatory biochemical pathway that involves molecular chaperones of the heat shock protein (HSP) family during homeostasis-threatening stressful situations (e.g., thermal, oxidative and metabolic stresses). The entry of SARS coronaviruses in target cells, on the other hand, aggravates the already-jeopardized HSR of this specific group of patients. In addition, cellular counterattack against virus involves interferon (IFN)-mediated inflammatory responses. Therefore, individuals with impaired HSR cannot resolve virus-induced inflammatory burst physiologically, being susceptible to exacerbated forms of inflammation, which leads to a fatal “cytokine storm”. Interestingly, some species of bats that are natural reservoirs of zoonotic viruses, including SARS-CoV-2, possess an IFN-based antiviral inflammatory response perpetually activated but do not show any sign of disease or cytokine storm. This is possible because bats present a constitutive HSR that is by far (hundreds of times) more intense and rapid than that of human, being associated with a high core temperature. Similarly in humans, fever is a physiological inducer of HSR while antipyretics, which block the initial phase of inflammation, impair the resolution phase of inflammation through the HSR. These findings offer a rationale for the reevaluation of patient care and fever reduction in SARS, including COVID-19.

show abstract

“…For example, in a local tumor microenvironment (TME), the secretome of lingering senescent cells can markedly promote malignancy of neighboring cancer cells, particularly chemoresistance, and cause chronic inflammation associated with many age-related disorders [7][8][9] . Despite limited therapeutic efficacy-promoting outcomes that depend on a given context 10 , the net effect of the SASP in advanced cancers far outweighs its beneficial contributions, ultimately accelerating disease progression 5,7 . Specifically, the harmful inflammation imposed by the SASP suggests that eliminating senescent cells or suppressing the SASP can be advantageous in multiple types of pathologies and not just cancer 8,9,11 .…”

Section: Introductionmentioning

confidence: 99%

KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype

Zhang

Long

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation, including epigenetic decoration of chromatin structure and functional modulation of bioactive components. Here we report that expression of the histone H3-specific demethylase KDM4 is upregulated in human stromal cells upon cellular senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation are correlated with adverse survival of cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq and expression profiling through RNA-seq reveal extensive reorganization of chromosomes and spatiotemporal reprogramming of the transcriptomic landscape, events responsible for development of the senescence-associated secretory phenotype (SASP). Selectively targeting KDM4 dampens the SASP of senescent stromal cells and enhances the apoptotic index of cancer cells in the treatment-damaged tumor microenvironment (TME), together prolonging overall survival of experimental animals. Our study supports the dynamic change of H3K9/H3K36 methylation marks during cellular senescence, identifies an unusually permissive chromatin state, unmasks KDM4 as a key modulator of the SASP, and presents a novel therapeutic avenue to manipulate cellular senescence and curtail age-related pathologies.

show abstract

Senescent Cells: Emerging Targets for Human Aging and Age-Related Diseases

Cited by 140 publications

References 135 publications

Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly

Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly

Suppressed anti-inflammatory heat shock response in high-risk COVID-19 patients: lessons from basic research (inclusive bats), light on conceivable therapies

KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype

Contact Info

Product

Resources

About