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The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient's age. Adults over 65 years of age represent 80% of hospitalizations and have a 23-fold greater risk of death than those under 65. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea, and from there the disease can progress to acute respiratory distress syndrome, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes and obesity increase the chances of fatal disease, but they alone do not explain why age is an independent risk factor. Here, we present the molecular differences between young, middle-aged and older people that may explain why COVID-19 is a mild illness in some but life-threatening in others. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase the survival of older people, not simply by inhibiting the virus, but by restoring patients' ability to clear the infection and effectively regulate immune responses.

Why does COVID-19 disproportionately affect older people?

Background— Adiponectin is an adipocyte-derived plasma protein that accumulates in the injured artery and has potential antiatherogenic properties. This study was designed to determine whether a decreased plasma adiponectin level (hypoadiponectinemia) can be independently associated with the prevalence of coronary artery disease (CAD). Methods and Results— The consecutive 225 male patients were enrolled from inpatients who underwent coronary angiography. Voluntary blood donors (n=225) matched for age served as controls. Plasma adiponectin levels in the CAD patients were significantly lower than those in the control subjects. Multiple logistic regression analysis including plasma adiponectin level, diabetes mellitus, dyslipidemia, hypertension, smoking habits, and body mass index revealed that hypoadiponectinemia was significantly and independently correlated with CAD (P<0.0088). The entire study population was categorized in quartiles based on the distribution of plasma adiponectin levels. The interquarti...

Association of Hypoadiponectinemia With Coronary Artery Disease in Men

Most cancers arise in individuals over the age of 60. As the world population is living longer and reaching older ages, cancer is becoming a substantial public health problem. It is estimated that, by 2050, more than 20% of the world's population will be over the age of 60 - the economic, healthcare and financial burdens this may place on society are far from trivial. In this Review, we address the role of the ageing microenvironment in the promotion of tumour progression. Specifically, we discuss the cellular and molecular changes in non-cancerous cells during ageing, and how these may contribute towards a tumour permissive microenvironment; these changes encompass biophysical alterations in the extracellular matrix, changes in secreted factors and changes in the immune system. We also discuss the contribution of these changes to responses to cancer therapy as ageing predicts outcomes of therapy, including survival. Yet, in preclinical studies, the contribution of the aged microenvironment to therapy response is largely ignored, with most studies designed in 8-week-old mice rather than older mice that reflect an age appropriate to the disease being modelled. This may explain, in part, the failure of many successful preclinical therapies upon their translation to the clinic. Overall, the intention of this Review is to provide an overview of the interplay that occurs between ageing cell types in the microenvironment and cancer cells and how this is likely to impact tumour metastasis and therapy response.

How the ageing microenvironment influences tumour progression

The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well-established clinical guidelines. Physicians are often forced to engage in cycles of "trial and error" that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are "aging faster" to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13080

Measuring biological aging in humans: A quest.

Aging is a complex process that results from a combination of environmental, genetic, and epigenetic factors. A chronic pro-inflammatory status is a pervasive feature of aging. This chronic low-grade inflammation occurring in the absence of overt infection has been defined as “inflammaging” and represents a significant risk factor for morbidity and mortality in the elderly. The low-grade inflammation persists even after reversing pro-inflammatory stimuli such as LDL cholesterol and the renin–angiotensin system (RAS). Recently, several possible sources of chronic low-grade inflammation observed during aging and age-related diseases have been proposed. Cell senescence and dysregulation of innate immunity is one such mechanism by which persistent prolonged inflammation occurs even after the initial stimulus has been removed. Additionally, the coagulation factor that activates inflammatory signaling beyond its role in the coagulation system has been identified. This signal could be a new source of chronic inflammation and cell senescence. Here, we summarized the factors and cellular pathways/processes that are known to regulate low-grade persistent inflammation in aging and age-related disease.

/pdf/source-of-chronic-inflammation-in-aging-o5takfw7rx.pdf

Source of Chronic Inflammation in Aging.

We previously reported that overexpression of full-length periostin, Pn-1, resulted in ventricular dilation with enhanced interstitial collagen deposition in a rat model. However, other reports have documented that the short-form splice variants Pn-2 (lacking exon 17) and Pn-4 (lacking exons 17 and 21) promoted cardiac repair by angiogenesis and prevented cardiac rupture after acute myocardial infarction. The apparently differing findings from those reports prompted us to use a neutralizing antibody to selectively inhibit Pn-1 by blockade of exon 17 in a rat acute myocardial infarction model. Administration of Pn neutralizing antibody resulted in a significant decrease in the infarcted and fibrotic areas of the myocardium, which prevented ventricular wall thinning and dilatation. The inhibition of fibrosis by Pn neutralizing antibody was associated with a significant decrease in gene expression of fibrotic markers, including collagen I, collagen III, and transforming growth factor-β1. Importantly, the number of α-smooth muscle actin-positive myofibroblasts was significantly reduced in the hearts of animals treated with Pn neutralizing antibody, whereas cardiomyocyte proliferation and angiogenesis were comparable in the IgG and neutralizing antibody groups. Moreover, the level of Pn-1 expression was significantly correlated with the severity of myocardial infarction. In addition, Pn-1, but not Pn-2 or Pn-4, inhibited fibroblast and myocyte attachment, which might account for the cell slippage observed during cardiac remodeling. Collectively, these results indicate that therapeutics that specifically inhibit Pn exon-17, via a neutralizing antibody or drug, without suppressing other periostin variants might offer a new class of medication for the treatment of acute myocardial infarction patients.

Selective Blockade of Periostin Exon 17 Preserves Cardiac Performance in Acute Myocardial Infarction.

Our previous study demonstrated that coagulation factor Xa (FXa) induced endothelial cell senescence, resulting in inflammation and impaired angiogenesis. This mechanism is dictated through protease-activated receptors, PARs, insulin-like growth factor-binding protein 5 (IGFBP-5), and p53. Activation of PARs contributes to the pathophysiology of several chronic inflammatory diseases, including atherosclerosis. Thus, we speculated that similar mechanism might participate in the progression of atherosclerotic plaques. In the present study, we successfully identified the cells that produced FX/Xa in atherosclerosis using human atherosclerotic plaques obtained from carotid endarterectomy. In situ hybridization for FX revealed that FX was generated in vascular smooth muscle cells (VSMC), inflammatory cells, and endothelial cells. Then, we examined the effects of FXa on the growth of VSMC in vitro. The present study revealed that chronic FXa stimulation significantly induced the senescence of VSMC with concomitant upregulation of IGFBP-5 and p53. Inhibition of FXa signaling with rivaroxaban or knock down of IGFBP-5 significantly reduced FXa-induced VSMC senescence and inflammatory cytokine production. Finally, we confirmed that FXa and IGFBP-5 are co-distributed in atherosclerotic plaques. In conclusion, induction of senescence of VSMC induced by locally produced FX/Xa may contribute to the progression of atherosclerosis.

/pdf/local-production-of-activated-factor-x-in-atherosclerotic-1iiwccwedv.pdf

Local Production of Activated Factor X in Atherosclerotic Plaque Induced Vascular Smooth Muscle Cell Senescence

Cellular senescence is the complex process of deterioration that drives the aging of an organism, resulting in the progressive loss of organ function and eventually phenotypic aging. Senescent cells undergo irreversible growth arrest, usually by inducing telomere shortening. Alternatively, senescence may also occur prematurely in response to various stress stimuli, such as oxidative stress, DNA damage, or activated oncogenes. Recently, it has been shown that IGF binding protein-5 (IGFBP-5) with the induction of the tumor suppressor p53 is upregulated during cellular senescence. This mechanism mediates interleukin-6/gp130-induced premature senescence in human fibroblasts, irradiation-induced premature senescence in human endothelial cells (ECs), and replicative senescence in human ECs independent of insulin-like growth factor I (IGF-I) and IGF-II. Additionally, a link between IGFBP-5, hyper-coagulation, and inflammation, which occur with age, has been implicated. Thus, IGFBP-5 seems to play decisive roles in controlling cell senescence and cell inflammation. In this review, we describe the accumulating evidence for this role of IGFBP-5 including our new finding.

/pdf/igf-binding-protein-5-induces-cell-senescence-g08ztw5iv2.pdf

IGF Binding Protein-5 Induces Cell Senescence.

Objective— Peripheral arterial disease is highly prevalent in the elderly and in the subjects with cardiovascular risk factors such as diabetes. Approximately 2% to 4% of those affected with peripheral arterial disease commonly complain of intermittent claudication. Cilostazol, a type III phosphodiesterase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of intermittent claudication. Cilostazol has been shown to be beneficial for the improvement of pain-free walking distance in patients with intermittent claudication in a series of randomized clinical trials. However, the underlying mechanism how cilostazol improved intermittent claudication symptoms is still unclear. Approach and Results— In this study, the effect of cilostazol on ischemic leg was investigated in mouse ischemic hindlimb model. Administration of cilostazol significantly increased the expression of hepatocyte growth factor (HGF), vascular endothelial growth factor, angiopoietin-1, and peroxisome proliferator-activated receptor-γ in vasculature. The capillary density in ischemic leg was also significantly increased in cilostazol treatment group when compared with control and aspirin treatment group. However, an increase in capillary density and the expression of growth factors was almost completely abolished by coadministration of HGF-neutralizing antibody, suggesting that cilostazol enhanced angiogenesis mainly through HGF. In vitro experiment revealed that cilostazol treatment increased HGF production in vascular smooth muscle cells via 2 major pathways: peroxisome proliferator-activated receptor-γ and cAMP pathways. Conclusions— Our data suggest that the favorable effects of cilostazol on ischemic leg might be through the angiogenesis through the induction of HGF via peroxisome proliferator-activated receptor-γ and cAMP pathways.

Induction of Angiogenesis by a Type III Phosphodiesterase Inhibitor, Cilostazol, Through Activation of Peroxisome Proliferator-Activated Receptor-γ and cAMP Pathways in Vascular Cells

Jun Muratsu

Papers

Source of Chronic Inflammation in Aging.

Selective Blockade of Periostin Exon 17 Preserves Cardiac Performance in Acute Myocardial Infarction.

Local Production of Activated Factor X in Atherosclerotic Plaque Induced Vascular Smooth Muscle Cell Senescence

IGF Binding Protein-5 Induces Cell Senescence.

Induction of Angiogenesis by a Type III Phosphodiesterase Inhibitor, Cilostazol, Through Activation of Peroxisome Proliferator-Activated Receptor-γ and cAMP Pathways in Vascular Cells