T cell fate decisions during memory cell generation with aging.

The defense against infectious diseases, either through natural immunity or after vaccinations, relies on the generation and maintenance of protective T cell memory. Naïve T cells are at the center of memory T cell generation during primary responses. Upon activation, they undergo a complex, highly regulated differentiation process towards different functional states. Naïve T cells maintained into older age have undergone epigenetic adaptations that influence their fate decisions during differentiation. We review age-sensitive, molecular pathways and gene regulatory networks that bias naïve T cell differentiation towards effector cell generation at the expense of memory and Tfh cells. As a result, T cell differentiation in older adults is associated with release of bioactive waste products into the microenvironment, higher stress sensitivity as well as skewing towards pro-inflammatory signatures and shorter life spans. These maladaptations not only contribute to poor vaccine responses in older adults but also fuel a more inflammatory state.

Potential relationship between cytomegalovirus and immunosenescence: Evidence from observational studies.

Immunosenescence (IS) occurs as a natural outcome of ageing and may be described as a decline in immune system flexibility and adaptability to sufficiently respond to new, foreign antigens. Potential factors that may precipitate IS include persistent herpesvirus infections, such as cytomegalovirus (CMV). Here, we conducted a review of the literature evaluating the potential association between CMV and IS. Twenty-seven epidemiologic studies that included direct comparisons between CMV-seropositive and CMV-seronegative immunocompetent individuals were analysed. The majority of these studies (n = 20) were conducted in European populations. The strength of evidence supporting a relationship between CMV, and various IS-associated immunologic endpoints was assessed. T-cell population restructuring was the most prominently studied endpoint, described in 21 studies, most of which reported a relationship between CMV and reduced CD4:CD8 T-cell ratio or modified CD8+ T-cell levels. Telomere length (n = 4) and inflammageing (n = 3) were less frequently described in the primary literature, and the association of these endpoints with CMV and IS was less pronounced. An emergent trend from our review is the potential effect modification of the CMV-IS relationship with both sex and age, indicating the importance of considering various effector variables when evaluating associations between CMV and IS. Our analysis revealed plausible mechanisms that may underlie the larger epidemiologic trends seen in the literature that support the indirect effect of CMV on IS. Future studies are needed to clarify CMV-associated and IS-associated immunologic endpoints, as well as in more diverse global and immunocompromised populations.

Sex-associated differences in cardiac ageing: Clinical aspects and molecular mechanisms.

Despite the extensive clinical and scientific advances in prevention, diagnostics and treatment, cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality worldwide for people aged 65 and over. Of all ageing-related diseases, CVD are responsible for almost one-third of deaths in the elderly, being above all cancers combined. Age is an independent and unavoidable risk factor contributing to the impairment of heart and blood vessels. As the average age of the population in industrialized countries has doubled in the last century, and almost a fifth of the world's population is predicted to be over 65 in the next decade, we can assume that the burden of CVD will fall primarily on the elderly. Evidence from basic and clinical science has shown that sex significantly influences the onset and severity of CVD. In women, CVD usually develop later than in men and with atypical symptomatology. After menopause, however, the incidence and severity of CVD increase in women, reaching equality in both sexes. Although intrinsic sexual dimorphism in cardiovascular ageing may contribute to the sex differences in CVD progression, the molecular mechanisms associated with cardiovascular ageing and their clinical value are not known in detail. In this review, we discuss the scientific knowledge available, focusing on structural, hormonal, genetic/epigenetic and inflammatory pathways, seeking to transfer these findings to the cardiovascular clinic in terms of prevention, diagnosis, prognosis and management of these pathologies and proposing possible validation of target specifics.

Development of Receptor for Advanced Glycation End Products (RAGE) ligands through target directed dynamic combinatorial chemistry: a novel class of possible antagonists.

RAGE is a transmembrane receptor of immunoglobulin family that can bind various endogenous and exogenous ligands, initiating the inflammatory downstream signaling pathways, including inflammaging. Therefore, RAGE represents an attractive drug target for age-related diseases. For the development of small-molecule RAGE antagonists, we employed protein-templated dynamic combinatorial chemistry (ptDCC) using RAGE's VC1 domain as a template, the first application of this approach in the context of RAGE. The affinities of DCC hits were validated using microscale thermophoresis. Subsequent screening against AGE2 (glyceraldehyde-modified AGE)-sRAGE (solubleRAGE) (AGE2-BSA/sRAGE) interaction using ELISA tests led to the identification of antagonists with micromolar potency. Our findings not only demonstrate the successful application of ptDCC on RAGE but also highlight its potential to address the pressing need for alternative strategies for the development of small-molecule RAGE antagonists, an area of research that has experienced a slowdown in recent years.

Centenarians, semi and supercentenarians, COVID-19 and Spanish flu: a serological assessment to gain insight into the resilience of older centenarians to COVID-19.

BACKGROUND: Although it is well known that the older people have been the most susceptible to COVID-19, there are conflicting data on the susceptibility of centenarians. Two epidemiological study have shown that older centenarians (> 101 years old at the time of the 2020 pandemic peak) are more resilient than the remaining centenarians, suggesting that this resilience might be linked to the 1918 Spanish Flu pandemic. To gain insight into this matter, specifically whether the resilience of older centenarians to SARS-CoV-2 infection is linked to the Spanish Flu they had been affected by, we conducted a retrospective serological study. This study examined serum samples from 33 centenarians, encompassing semi- (aged > 104 < 110 years, N = 7) and supercentenarians (aged > 109 years, N = 4), born between 1905 and 1922, against both SARS-CoV-2 and 1918 H1N1 pseudotype virus. RESULTS: Anamnestic and laboratory data suggest that SARS-CoV-2 infection occurred in 8 centenarians. The infection appeared to have been asymptomatic or mild, and hospitalization was not required, despite 3 out of 8 being between 109 and 110 years old. The levels of anti-spike antibodies in centenarians infected and/or vaccinated were higher, although not significantly, than those produced by a random sample of seventy-year-old individuals used as controls. All centenarians had antibody levels against the 1918 H1N1 virus significantly higher (almost 50 times) than those observed in the quoted group of seventy-year-old subjects, confirming the key role in maintaining immunological memory from a priming that occurred over 100 years ago. Centenarians whose blood was collected prior to the pandemic outbreak demonstrated neutralising antibodies against the 1918 H1N1 virus, but all these subjects tested negative for SARS-CoV-2. CONCLUSION: This retrospective study shows that older centenarians are quite resilient to COVID-19, as they are capable of producing good levels of neutralising antibodies and experiencing mild or asymptomatic disease. This could be attributed to the 1918 Spanish flu pandemic through mechanisms other than the presence of cross-reactive antibodies between the 1918 H1N1 virus and SARS-CoV-2. Another possibility is that the association is purely temporal, solely correlated with the advanced age of resilient centenarians compared to those born after 1918, since older centenarians are known to have better control of immune-inflammatory responses.

Inflammatory markers and frailty in home-dwelling elderly, a cross-sectional study.

BACKGROUND: Low-grade, chronic inflammation during ageing, ("inflammageing"), is suggested to be involved in the development of frailty in older age. However, studies on the association between frailty, using the frailty index definition, and inflammatory markers are limited. The aim of this study was to investigate the relationship between inflammatory markers and frailty index (FI) in older, home-dwelling adults. METHOD: Home-dwelling men and women aged ≥ 70 years old, living in South-East Norway were recruited and included in a cross-sectional study. The FI used in the current study was developed according to Rockwood's frailty index and included 38 variables, resulting in an FI score between 0 and 1 for each participant. Circulating inflammatory markers (IL-6, CRP, IGF-1, cystatin C, cathepsin S, and glycoprotein Acetyls) were analyzed from non-fasting blood samples using ELISA. Whole-genome PBMC transcriptomics was used to study the association between FI score and inflammation. RESULTS: The study population comprised 403 elderly (52% women), with a median age of 74 years and a mean BMI of 26.2 kg/m2. The mean FI score for the total group was 0.15 (range 0.005-0.56). The group was divided into a frail group (FI score ≥ 0.25) and non-frail group. After adjusting for BMI, age, sex, and smoking in the whole group, IL-6, cathepsin S, cystatin C, and Gp-acetyls remained significant associated to FI score (IL-6: 0.002, 95% CI: 0.001, 0.002, cathepsin S: 6.7e-06, 95% CI 2.44e-06, 0.00001, cystatin C: 0.004, 95% CI: 0.002, 0.006, Gp- Acetyls: 0.09, 95% CI: 0.05, 0.13, p < 0.01 for all), while CRP and IGF-1 were not (0.0003, 95% CI: -00001, 0.0007, p = 0.13, (-1.27e-06), 95% CI: (-0.0003), 0.0003, p = 0.99). There was a significant association between FI score and inflammatory markers, and FI score and monocyte-specific gene expression. CONCLUSIONS: We found an association between FI score and inflammatory markers, and between FI score and monocyte-specific gene expression among elderly subjects above 70 years of age. Whether inflammation is a cause or consequence of frailty and whether the progression of frailty can be attenuated by reducing inflammation remains to be clarified.

Introduction: Progression of the Science of Ageing.

We outline the progression of ageing research from ancient history to present day geroscience. Calorie restriction, genetic mutations, and the involvement of the sirtuins are highlighted, along with pharmaceutical interventions, in particular rapamycin. At the cellular level, replicative senescence and telomere shortening are presented in the history of ageing studies. We discuss the roles of macromolecular damage in ageing including damage to nuclear, and mitochondrial DNA, epigenetic and protein damage. The importance inflammation during ageing "inflammageing" is becoming increasingly recognized. Omics-based biomarkers are now proving to be a promising approach, along with comparative studies on long-lived animals. The science is getting closer to understanding the mechanisms of ageing and developing reliable interventions to improve human health.

The role of transposable elements in aging and cancer.

Transposable elements (TEs) constitute a large portion of the human genome. Various mechanisms at the transcription and post-transcription levels developed to suppress TE activity in healthy conditions. However, a growing body of evidence suggests that TE dysregulation is involved in various human diseases, including age-related diseases and cancer. In this review, we explained how sensing TEs by the immune system could induce innate immune responses, chronic inflammation, and following age-related diseases. We also noted that inflammageing and exogenous carcinogens could trigger the upregulation of TEs in precancerous cells. Increased inflammation could enhance epigenetic plasticity and upregulation of early developmental TEs, which rewires the transcriptional networks and gift the survival advantage to the precancerous cells. In addition, upregulated TEs could induce genome instability, activation of oncogenes, or inhibition of tumor suppressors and consequent cancer initiation and progression. So, we suggest that TEs could be considered therapeutic targets in aging and cancer.

Biological Effects of "Inflammageing" on Human Oral Cells: Insights into a Potential Confounder of Age-Related Diseases.

OBJECTIVES: The term "inflammageing" describes the process of inflammation-induced aging that leads living cells to a state of permanent cell cycle arrest due to chronic antigenic irritation. This in vitro study aimed to shed light on the mechanisms of "inflammageing" on human oral cells. METHODS: Primary cultures of human gingival fibroblasts (hGFs) were exposed to variable pro-inflammatory stimuli, including lipopolysaccharide (LPS), Tumor Necrosis Factor-alpha (TNFa), and gingival crevicular fluid (GCF) collected from active periodontal pockets of systemically healthy patients. Inflammageing was studied through two experimental models, employing either late-passage ("aged") cells (p. 10) that were exposed to the pro-inflammatory stimuli or early-passage ("young") cells (p. 1) continuously exposed during a period of several passages (up to p. 10) to the above-mentioned stimuli. Cells were evaluated for the expression of beta-galactosidase activity (histochemical staining), senescence-associated genes (qPCR analysis), and biomarkers related to a Senescence-Associated Secretory Phenotype (SASP), through proteome profile analysis and bioinformatics. RESULTS: A significant increase (p < 0.05) in beta-galactosidase-positive cells was observed after exposure to each pro-inflammatory stimulus. The senescence-associated gene expression included upregulation for CCND1 and downregulation for SUSD6, and STAG1, a profile typical for cellular senescence. Overall, pro-inflammatory priming of late-passage cells caused more pronounced effects in terms of senescence than long-term exposure of early-passage cells to these stimuli. Proteomic analysis showed induction of SASP, evidenced by upregulation of several pro-inflammatory proteins (IL-6, IL-10, IL-16, IP-10, MCP-1, MCP-2, M-CSF, MIP-1a, MIP-1b, TNFb, sTNF-RI, sTNF-RII, TIMP-2) implicated in cellular aging and immune responses. The least potent impact on the induction of SASP was provoked by LPS and the most pronounced by GCF. CONCLUSION: This study demonstrates that long-term exposure of hGFs to various pro-inflammatory signals induced or accelerated cellular senescence with the most pronounced impact noted for the late-passage cells. The outcome of these analyses provides insights into oral chronic inflammation as a potential confounder of age-related diseases.

Mortality in Greenlanders with chronic hepatitis B virus infection.

In-depth reviewing of all medical records and clinical databases concluded a 7-year shorter lifespan among Greenlanders infected with hepatitis B virus (HBV) compared with non-infected. Mortality did not associate with liver disease or any other specific disease entity. A possible mechanism for the reduced lifespan is subclinical inflammation that may be augmented by chronic viral infection. We hypothesized that chronic HBV infection contributes to this process causing a reduced life span. We added measurement of two markers of inflammation to the 10-year follow-up on our study of HBV among 50- through 69-years-old subjects in Greenland. The markers were YKL40 related to liver disease and hsCRP as a global marker of inflammation. Survival was evaluated using Cox regression with time until death entered as dependent variable and age, sex, smoking, alcohol intake, BMI, the presence of HBsAg and one marker of inflammation as explanatory variables. Forty-eight percent of participants with chronic HBV infection were alive after 10 years compared with 65% of participants without infection (p = 0.003). Survival associated with age (p < 0.001), BMI (p = 0.003) and both YKL40 and hsCRP (both, p < 0.001). Harbouring HBV influenced 10-year survival in the Cox regression after adjusting for age, sex, BMI, smoking, alcohol intake and inflammation. In conclusion, chronic low-grade inflammation and being infected with HBV were independent markers of mortality in otherwise healthy subjects. Thus, the 7-year shorter lifespan among Greenlanders with chronic HBV infection seems related to the long-lasting infection. Our findings call for caution in perceiving a chronic infection as benign.

Food for healthier aging: power on your plate.

Inflammageing is a persistent low-level inflammatory burden that accompanies age-related dysregulation of the immune system during normative aging and within the diseasome of aging. A healthy diet containing a balanced amount of macronutrients, vitamins and minerals, adequate in calories and rich in poly(phenols), has an essential role in mitigating the effects of inflammageing and extending healthspan through modulation of the activity of a range of factors. These include transcription factors, such as nuclear factor erythroid-derived 2 related factor 2 (Nrf2) and nuclear factor-κB (NF-kB), the inflammasome and the activities of the gut microbiota. The aim of this narrative review is to discuss the potential of food to ameliorate the effects of the diseasome of aging.

Pro-resolving lipid mediators: Agents of anti-ageing?

Inflammation is an essential response to injury and its timely and adequate resolution permits tissue repair and avoidance of chronic inflammation. Ageing is associated with increased inflammation, sub-optimal resolution and these act as drivers for a number of ageing-associated pathologies. We describe the role played by specialised proresolving lipid mediators (SPMs) in the resolution of inflammation and how insufficient levels of these mediators, or compromised responsiveness may play a role in the pathogenesis of many ageing-associated pathologies, e.g. Alzheimer's Disease, atherosclerosis, obesity, diabetes and kidney disease. Detailed examination of the resolution phase of inflammation highlights the potential to harness these lipid mediators and or mimetics of their bioactions, in particular, their synthetic analogues to promote effective resolution of inflammation, without compromising the host immune system.

Potentially Beneficial Effects on Healthy Aging by Supplementation of the EPA-Rich Microalgae Phaeodactylum tricornutum or Its Supernatant-A Randomized Controlled Pilot Trial in Elderly Individuals.

Dietary supplements that promote healthy aging are mostly warranted in an aging society. Because of age-related risks, anti-inflammatory and anti-oxidative agents such as microalgae are potential candidates for intervention. In a randomized controlled trial, we tested Phaeodactylum tricornutum (PT), a microalgae rich in eicosapentaenoic acid (EPA), carotenoids, vitamins, and ß-glucans, cultured in bioreactors. In this pilot trial, 19 healthy elderly received supplements for two weeks based on either the whole PT (A), the ß-1,3-glucan-rich PT supernatant (SupB), the combination thereof (A+SupB), or a Comparator product (Comp). The primary outcome variable plasma interleukin-6 was reduced after treatment with A+SupB compared to the Comp group (p = 0.04). The mobility parameters 5 s sit-to-stand test (p = 0.04 in the A group) and by trend gait speed (p = 0.08 in the A+SupB diet) were improved compared to Comp. No treatment effects were observed for fatty acids, compared to Comp but omega-6 to -3 fatty acid ratio (p = 0.006) and arachidonic acid/EPA ratio (p = 0.006) were reduced within group A+SupB. Further, the SupB study product reduced faecal zonulin (p = 0.03) compared to the Comp. The data revealed an anti-inflammatory and potentially anti-oxidative effect of particular PT preparations, suggesting that they might be suitable for effects in healthy elderly.

Endothelial Dysfunction and Chronic Inflammation: The Cornerstones of Vascular Alterations in Age-Related Diseases.

Vascular diseases of the elderly are a topic of enormous interest in clinical practice, as they have great epidemiological significance and lead to ever-increasing healthcare expenditures. The mechanisms underlying these pathologies have been increasingly characterized over the years. It has emerged that endothelial dysfunction and chronic inflammation play a diriment role among the most relevant pathophysiological mechanisms. As one can easily imagine, various processes occur during aging, and several pathways undergo irreversible alterations that can promote the decline and aberrations that trigger the diseases above. Endothelial dysfunction and aging of circulating and resident cells are the main characteristics of the aged organism; they represent the framework within which an enormous array of molecular abnormalities occur and contribute to accelerating and perpetuating the decline of organs and tissues. Recognizing and detailing each of these dysfunctional pathways is helpful for therapeutic purposes, as it allows one to hypothesize the possibility of tailoring interventions to the damaged mechanism and hypothetically limiting the cascade of events that drive the onset of these diseases. With this paper, we have reviewed the scientific literature, analysing the pathophysiological basis of the vascular diseases of the elderly and pausing to reflect on attempts to interrupt the vicious cycle that connotes the diseases of aging, laying the groundwork for therapeutic reasoning and expanding the field of scientific research by moving from a solid foundation.

Immunosenescence and multiple sclerosis.

Changes in the immune system associated with ageing are known as immunosenescence. This is characterised by a decline in immune response, chronic inflammation and an increased risk of autoimmune diseases. A chronic inflammatory process with persistent production of proinflammatory mediators increases the risk for morbidity and mortality related to age, and has been dubbed 'inflamm-ageing'. Immunosenescence is associated with a decrease in the number of naive T and B cells, NK cells and disruption of the pro- and anti-inflammatory balance by changes in the production of cytokines. In fact, ageing of the immune system has a complex network of underlying causes which include not only natural mechanisms of senescence but also chronic disorders, lifestyle, environmental and epigenetic factors, and infections. Moreover, immunosenescence has an influence on the course of chronic diseases which have an onset in young adults, such as multiple sclerosis (MS). Current disease modifying therapies (DMTs) in MS aim to reduce the frequency of relapses and to slow disease progression, but they do not necessarily stop the accumulation of disability related to disease progression. Some features of immunosenescence found in aged healthy controls are already observed in MS patients at a younger age. The older population is characterised by an increased susceptibility to infections, a poor response to vaccinations, and a higher risk of developing cancer, vascular diseases and neurodegeneration. Immunosenescence is an important factor influencing the course of MS, and the safety and effectiveness of DMTs. The relationship between the pathogenic process underlying the development of MS and immunosenescence requires further investigation.

MDSCs, ageing and inflammageing.

The challenge of distinguishing between changes attributable to ageing and those attributable to pathology is even greater for the immune system than for many other organs, and this is especially true for myeloid-derived suppressor cells (MDSCs). Hematopoiesis is different in older adults with a bias towards myelopoiesis, and older adults also manifest "inflammageing" exacerbated by disease and contributing to MDSC induction. Hence, at least in humans, one can only investigate MDSCs in the context of ageing and disease states, and not in the context of ageing processes per se. This contribution provides a brief overview of the literature on MDSCs and ageing in humans.

TNF-α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm-ageing.

AIMS: Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm-aging as a mediator and potential therapeutic target. METHODS: 3 months- (young) and 18-20 months-old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF-α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF- α were assessed in patients with ischemic stroke and correlated with age and outcome. RESULTS: Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood-brain barrier in old mice, i.e. increased post-stroke degradation of endothelial tight junctions and expression of tight junctions-digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF-α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF-α plasma levels which correlated with worsened short-term neurological outcome as well as with age. CONCLUSIONS: This study identifies TNF-α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm-aging as a mechanism of age-related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.

Dysregulation of leukocyte trafficking in ageing: Causal factors and possible corrective therapies.

Ageing is a universal biological phenomenon that is accompanied by the development of chronic, low-grade inflammation and remodelling of the immune system resulting in compromised immune function. In this review, we explore how the trafficking of innate and adaptive immune cells under homeostatic and inflammatory conditions is dysregulated in ageing. We particularly highlight the age-related changes in the expression of adhesion molecules and chemokine receptor/ligands, and the accumulation of senescent cells that drive modulated leukocyte trafficking. These age-related changes to leukocyte trafficking are multifactorial and specific to leukocyte subset, tissue, type of vascular bed, and inflammatory status. However, dysregulated leukocyte trafficking ultimately affects immune responses in older adults. We therefore go on to discuss approved drugs, including anti-integrins, anti-chemokines and statins, as well as novel therapeutics that may be used to target dysregulated leukocyte trafficking in ageing, improve immune responses and delay the onset of age-related diseases.

An evaluation of the recognised systemic inflammatory biomarkers of chronic sub-optimal inflammation provides evidence for inflammageing (IFA) during multiple sclerosis (MS).

The pathogenesis of the human demyelinating disorder multiple sclerosis (MS) involves the loss of immune tolerance to self-neuroantigens. A deterioration in immune tolerance is linked to inherent immune ageing, or immunosenescence (ISC). Previous work by the author has confirmed the presence of ISC during MS. Moreover, evidence verified a prematurely aged immune system that may change the frequency and profile of MS through an altered decline in immune tolerance. Immune ageing is closely linked to a chronic systemic sub-optimal inflammation, termed inflammageing (IFA), which disrupts the efficiency of immune tolerance by varying the dynamics of ISC that includes accelerated changes to the immune system over time. Therefore, a shifting deterioration in immunological tolerance may evolve during MS through adversely-scheduled effects of IFA on ISC. However, there is, to date, no collective proof of ongoing IFA during MS. The Review addresses the constraint and provides a systematic critique of compelling evidence, through appraisal of IFA-related biomarker studies, to support the occurrence of a sub-optimal inflammation during MS. The findings justify further work to unequivocally demonstrate IFA in MS and provide additional insight into the complex pathology and developing epidemiology of the disease.

Different aspects of frailty and COVID-19: points to consider in the current pandemic and future ones.

BACKGROUND: Older adults at a higher risk of adverse outcomes and mortality if they get infected with Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). These undesired outcomes are because ageing is associated with other conditions like multimorbidity, frailty and disability. This paper describes the impact of frailty on coronavirus disease 2019 (COVID-19) management and outcomes. We also try to point out the role of inflamm-ageing, immunosenescence and reduced microbiota diversity in developing a severe form of COVID-19 and a different response to COVID-19 vaccination among older frail adults. Additionally, we attempt to highlight the impact of frailty on intensive care unit (ICU) outcomes, and hence, the rationale behind using frailty as an exclusion criterion for critical care admission. Similarly, the importance of using a time-saving, validated, sensitive, and user-friendly tool for frailty screening in an acute setting as COVID-19 triage. We performed a narrative review. Publications from 1990 to March 2021 were identified by searching the electronic databases MEDLINE, CINAHL and SCOPUS. Based on this search, we have found that in older frail adults, many mechanisms contribute to the severity of COVID-19, particularly cytokine storm; those mechanisms include lower immunological capacity and status of ongoing chronic inflammation and reduced gut microbiota diversity. Higher degrees of frailty were associated with poor outcomes and higher mortality rates during and after ICU admission. Also, the response to COVID-19 vaccination among frail older adults might differ from the general population regarding effectiveness and side effects. Researches also had shown that there are many tools for identifying frailty in an acute setting that could be used in COVID-19 triage, and before ICU admission, the clinical frailty scale (CFS) was the most recommended tool. CONCLUSION: Older frail adults have a pre-existing immunopathological base that puts them at a higher risk of undesired outcomes and mortality due to COVID-19 and poor response to COVID-19 vaccination. Also, their admission in ICU should depend on their degree of frailty rather than their chronological age, which is better to be screened using the CFS.