scholarly journals New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms

2020 ◽  
Author(s):  
Tamar Tchkonia ◽  
Allyson K Palmer ◽  
James L Kirkland
Keyword(s):  
Cellular Senescence ◽  
The Elderly ◽  
Protein Accumulation ◽  
Unitary Theory ◽  
Research Attention ◽  
New Horizons ◽  
Related Disease ◽  
Age Related ◽  
Metabolite Generation ◽  
Aging Mechanisms

Abstract The elderly population is increasing faster than other segments of the population throughout the world. Age is the leading predictor for most chronic diseases and disorders, multimorbidity, geriatric syndromes, and impaired ability to recover from accidents or illnesses. Enhancing the duration of health and independence, termed healthspan, would be more desirable than extending lifespan merely by prolonging the period of morbidity toward the end of life. The geroscience hypothesis posits that healthspan can be extended by targeting fundamental aging mechanisms, rather than attempting to address each age-related disease one at a time, only so the afflicted individual survives disabled and dies shortly afterward of another age-related disease. These fundamental aging mechanisms include, among others, chronic inflammation, fibrosis, stem cell/ progenitor dysfunction, DNA damage, epigenetic changes, metabolic shifts, destructive metabolite generation, mitochondrial dysfunction, misfolded or aggregated protein accumulation, and cellular senescence. These processes appear to be tightly interlinked, as targeting any one appears to affect many of the rest, underlying our Unitary Theory of Fundamental Aging Mechanisms. Interventions targeting many fundamental aging processes are being developed, including dietary manipulations, metformin, mTOR (mechanistic target of rapamycin) inhibitors, and senolytics, which are in early human trials. These interventions could lead to greater healthspan benefits than treating age-related diseases one at a time. To illustrate these points, we focus on cellular senescence and therapies in development to target senescent cells. Combining interventions targeting aging mechanisms with disease-specific drugs could result in more than additive benefits for currently difficult-to-treat or intractable diseases. More research attention needs to be devoted to targeting fundamental aging processes.

scholarly journals Rescuing Immunosenescence via Non-Specific Vaccination

Immuno ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 231-239
Author(s):  
Alexander I. Mosa
Keyword(s):  
Immune Responses ◽  
The Elderly ◽  
Short Review ◽  
Functional Markers ◽  
Healthy Life ◽  
Related Disease ◽  
Age Related ◽  
Population Vulnerability ◽  
Mechanistic Basis ◽  
Promising Avenue

Discrepancies in lifespan and healthy-life span are predisposing populations to an increasing burden of age-related disease. Accumulating evidence implicates aging of the immune system, termed immunosenescence, in the pathogenesis of multiple age-related diseases. Moreover, immune dysregulation in the elderly increases vulnerability to infection and dampens pathogen-specific immune responses following vaccination. The health challenges manifesting from these age related deficits have been dramatically exemplified by the current SARS-CoV-2 pandemic. Approaches to either attenuate or reverse functional markers of immunosenescence are therefore urgently needed. Recent evidence suggests systemic immunomodulation via non-specific vaccination with live-attenuated vaccines may be a promising avenue to at least reduce aged population vulnerability to viral infection. This short review describes current understanding of immunosenescence, the historical and mechanistic basis of vaccine-mediated immunomodulation, and the outstanding questions and challenges required for broad adoption.

scholarly journals Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuki Saito ◽  
Takako S. Chikenji
Keyword(s):  
Skeletal Muscle ◽  
Cellular Senescence ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Neuromuscular Disorders ◽  
Muscle Stem Cells ◽  
Related Disease ◽  
Tissue Degeneration ◽  
Cycle Arrest ◽  
Age Related

Skeletal muscle undergoes vigorous tissue remodeling after injury. However, aging, chronic inflammatory diseases, sarcopenia, and neuromuscular disorders cause muscle loss and degeneration, resulting in muscular dysfunction. Cellular senescence, a state of irreversible cell cycle arrest, acts during normal embryonic development and remodeling after tissue damage; when these processes are complete, the senescent cells are eliminated. However, the accumulation of senescent cells is a hallmark of aging tissues or pathological contexts and may lead to progressive tissue degeneration. The mechanisms responsible for the effects of senescent cells have not been fully elucidated. Here, we review current knowledge about the beneficial and detrimental effects of senescent cells in tissue repair, regeneration, aging, and age-related disease, especially in skeletal muscle. We also discuss how senescence of muscle stem cells and muscle-resident fibro-adipogenic progenitors affects muscle pathologies or regeneration, and consider the possibility that immunosenescence leads to muscle pathogenesis. Finally, we explore senotherapy, the therapeutic targeting of senescence to treat age-related disease, from the standpoint of improving muscle regeneration.

scholarly journals Senolytics Reduce Coronavirus-Related Mortality in Old Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 247-248
Author(s):  
Christina Camell
Keyword(s):  
Viral Infection ◽  
Cellular Senescence ◽  
Chronically Ill ◽  
The Elderly ◽  
Viral Antibodies ◽  
Age Related ◽  
Old Mice ◽  
Multiple Chronic Diseases ◽  
Pathogen Exposure ◽  
Related Mortality

Abstract The elderly and chronically ill are among groups at the highest risk for morbidity and mortality to several infections, including SARs-CoV-2. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation with nearly 100% mortality. Targeting SCs using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased anti-viral antibodies. Thus, reducing the SC burden in diseased or aged individuals should enhance resilience and reduce mortality following viral infection, including SARS-CoV-2.

Pathogenesis and clinical implications of HIV-related anemia in 2013

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 377-381 ◽  
Author(s):  
Amanda J. Redig ◽  
Nancy Berliner
Keyword(s):  
Antiretroviral Therapy ◽  
Accelerated Aging ◽  
The Elderly ◽  
Chronic Obstructive ◽  
Combination Antiretroviral Therapy ◽  
Obstructive Pulmonary Disease ◽  
Related Disease ◽  
Age Related ◽  
Entry Points ◽  
The Face

AbstractAnemia is a common feature of HIV-related disease and has been uniformly demonstrated to be an independent predictor of morbidity and mortality. Although anemia often responds to combination antiretroviral therapy, many patients remain anemic despite therapy and such persistent anemia continues to negatively affect prognosis regardless of drug response. Anemia is also a common feature of normal aging. We postulate that the pathophysiology of anemia in HIV, especially that which persists in the face of combination antiretroviral therapy, is a reflection of underlying proinflammatory pathways that are also thought to contribute to anemia in the elderly, as well as other age-related chronic diseases such as cardiovascular disease and chronic obstructive pulmonary disease. This suggests that HIV induces inflammatory pathways that are associated with a pattern of accelerated aging and that anemia is a biomarker of these processes. A better understanding of the pathophysiology of HIV-related anemia may provide important entry points for improving the chronic manifestations of HIV-related disease.

scholarly journals Cellular senescence in aging and age-related disease: from mechanisms to therapy

2015 ◽  
Vol 21 (12) ◽  
pp. 1424-1435 ◽  
Author(s):  
Bennett G Childs ◽  
Matej Durik ◽  
Darren J Baker ◽  
Jan M van Deursen
Keyword(s):  
Cellular Senescence ◽  
Related Disease ◽  
Age Related

scholarly journals Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Keng Siang Lee ◽  
Shuxiao Lin ◽  
David A. Copland ◽  
Andrew D. Dick ◽  
Jian Liu
Keyword(s):  
Retinal Pigment Epithelium ◽  
Macular Degeneration ◽  
Cellular Senescence ◽  
Vision Loss ◽  
Inflammatory Responses ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Age Related

AbstractAge-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed “chronic” senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

scholarly journals Modulation of Bacterial Pathogenesis by Oppressive Aging Factors: Insights into Host-Pneumococcal Interaction Strategies

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Pooja Shivshankar
Keyword(s):  
Cellular Senescence ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
The Elderly ◽  
Receptor Expression ◽  
Chronic Obstructive ◽  
Related Phenomenon ◽  
Aged Mice ◽  
Inflammatory Status ◽  
Age Related

Streptococcus pneumonia, (Spn, the pneumococcus), is the leading cause of community-acquired pneumonia (CAP) and is responsible for 15–40% deaths in the elderly worldwide. A primed inflammatory status is a significant risk factor for the increased severity of infectious diseases among the elderly (≥65 years of age). Studies have shown that expression of host receptors that the pneumococci bind to invade the tissues are increased thereby increasing the susceptibility to pneumococcal challenge in aged mice. Cellular senescence, an age-related phenomenon that leads to cell cycle arrest may also contribute to increased inflammation in aged mice. Evidence of cellular senescence in aged lungs of humans and mice adds credits to the concept of inflammaging and enhanced bacterial ligands expression during aging. Furthermore, cell senescence has been shown to occur in age-associated lung pathologies such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) that may predispose the elderly to pathogenic assaults, including S. pneumoniae. This review highlights the aspects of: chronic inflammation in the aged population; contribution of cellular senescence to age-associated inflammation and their impact on host receptor expression; and, increased susceptibility of fibrosis and emphysematous lesions-bearing lungs to microbial infections.

scholarly journals Senolytics reduce coronavirus-related mortality in old mice

Science ◽  
2021 ◽  
pp. eabe4832
Author(s):  
Christina D. Camell ◽  
Matthew J. Yousefzadeh ◽  
Yi Zhu ◽  
Larissa G. P. Langhi Prata ◽  
Matthew A. Huggins ◽  
...  
Keyword(s):  
Viral Infection ◽  
Cellular Senescence ◽  
Viral Entry ◽  
Viral Gene Expression ◽  
Chronically Ill ◽  
The Elderly ◽  
Viral Gene ◽  
Age Related ◽  
Molecular Patterns ◽  
Old Mice

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically-ill to SARS-CoV-2-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnC) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 Spike protein-1, increasing expression of viral entry proteins and reducing anti-viral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation with nearly 100% mortality. Targeting SnCs using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased anti-viral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality following viral infection, including SARS-CoV-2.

scholarly journals The Emerging Role of Senescence in Ocular Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-19 ◽  
Author(s):  
Parameswaran G. Sreekumar ◽  
David R. Hinton ◽  
Ram Kannan
Keyword(s):  
Cellular Senescence ◽  
Age Related Macular Degeneration ◽  
Bioactive Molecules ◽  
Surrounding Tissue ◽  
New Members ◽  
Age Related ◽  
Reasonable Evidence ◽  
Aging Mechanisms ◽  
Cellular Stresses

Cellular senescence is a state of irreversible cell cycle arrest in response to an array of cellular stresses. An important role for senescence has been shown for a number of pathophysiological conditions that include cardiovascular disease, pulmonary fibrosis, and diseases of the skin. However, whether senescence contributes to the progression of age-related macular degeneration (AMD) has not been studied in detail so far and the present review describes the recent research on this topic. We present an overview of the types of senescence, pathways of senescence, senescence-associated secretory phenotype (SASP), the role of mitochondria, and their functional implications along with antisenescent therapies. As a central mechanism, senescent cells can impact the surrounding tissue microenvironment via the secretion of a pool of bioactive molecules, termed the SASP. An updated summary of a number of new members of the ever-growing SASP family is presented. Further, we introduce the significance of mechanisms by which mitochondria may participate in the development of cellular senescence. Emerging evidence shows that extracellular vesicles (EVs) are important mediators of the effects of senescent cells on their microenvironment. Based on recent studies, there is reasonable evidence that senescence could be a modifiable factor, and hence, it may be possible to delay age-related diseases by modulating basic aging mechanisms using SASP inhibitors/senolytic drugs. Thus, antisenescent therapies in aging and age-related diseases appear to have a promising potential.

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