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.

Expert Consensus on Prevention and Treatment of Aging-Related Gonadal Dysfunction.

Aging-related hypogonadism involves complex mechanisms in humans, predominantly relating to the decline of multiple hormones and senile gonads. Late-onset hypogonadism (LOH) and erectile dysfunction (ED) are the main manifestations in men, while premature ovarian insufficiency (POI) and menopause are the main forms in women. Anti-aging measures include lifestyle modification and resistance training, hormonal supplementation, stem cell therapy, metformin, and rapamycin. In this expert consensus, the mechanisms, efficacy, and side effects of stem cell therapy on aging gonadal function are reviewed. Furthermore, various methods of stem cell therapy, administered intravenously, intracavernously, and intra-ovarially, are exemplified in detail. More clinical trials on aging-related gonadal dysfunction are required to solidify the foundation of this topic.

Sex and Gender in Ageing and Longevity: Highlights From an International Course.

Gender medicine is a multidisciplinary science and represents an important perspective for pathophysiological and clinical studies in the third millennium. Here, it is provided an overview of the topics discussed in a recent course on the Role of Sex and Gender in Ageing and Longevity. The paper highlights three themes discussed in the course, i.e., the interaction of gender/sex with, i) the pathophysiology of age-related diseases; ii), the role of genetics and epigenetics in ageing and longevity and, iii) the immune responses of older people to pathogens, vaccines, autoantigens, and allergens. Although largely unexplored, it is clear that sex and gender are modulators of disease biology and treatment outcomes. It is becoming evident that men and women should no longer be considered as subgroups, but as biologically distinct groups of patients deserving consideration for specific therapeutic approaches.

Senotherapeutics to Counteract Senescent Cells Are Prominent Topics in the Context of Anti-Ageing Strategies.

Cellular senescence is implicated in ageing and associated with a broad spectrum of age-related diseases. Importantly, a cell can initiate the senescence program irrespective of the organism's age. Various stress signals, including those defined as ageing hallmarks and alterations leading to cancer development, oncogene activation, or loss of cancer-suppressive functions, can trigger cellular senescence. The primary outcome of these alterations is the activation of nuclear factor (NF)-κB, thereby inducing the senescence-associated secretory phenotype (SASP). Proinflammatory cytokines and chemokines, components of this phenotype, contribute to chronic systemic sterile inflammation, commonly referred to as inflamm-ageing. This inflammation is linked to age-related diseases (ARDs), frailty, and increased mortality in older individuals. Additionally, senescent cells (SCs) accumulate in multiple tissues with age and are believed to underlie the organism functional decline, as demonstrated by models. An escalating effort has been dedicated to identify senotherapeutics that selectively target SCs by inducing apoptosis; these drugs are termed senolytics. Concurrently, small molecules that suppress senescent phenotypes without causing cell death are known as senomorphics. Both natural and synthetic senotherapeutics, along with immunotherapies employing immune cell-mediated clearance of SCs, currently represent the most promising strategies to combat ageing and ARDs. Indeed, it is fascinating to observe that information regarding the immune reaction to SCs indicates that regulation by specific lymphocyte subsets, elevated in the oldest centenarians, plays a role in attaining extreme longevity. Regardless, the application of methods already utilized in cancer treatment, such as CAR cells and monoclonal antibodies, broadens the spectrum of potential approaches to be utilized.

Sicilian semi- and supercentenarians: age-related Tγδ cell immunophenotype contributes to longevity trait definition.

The immune system of semi- (from ≥105 to <110 years old) and supercentenarians (≥110 years old), i.e. oldest centenarians, is thought to have characteristics that allow them to reach extreme longevity in relatively healthy status. Thus, we investigated variations of the two principal subsets of Tγδ, Vδ1, and Vδ2, and their functional subsets using the markers defining Tαß cells, i.e. CD27, CD45RA, in a cohort of 28 women and 26 men (age range 19-110 years), including 11 long-living individuals (from >90 years old to<105 years old), and eight oldest centenarians (≥105 years old), all of them were previously analysed for Tαß and NK cell immunophenotypes on the same blood sample collected on recruitment day. Naïve Vδ1 and Vδ2 cells showed an inverse relationship with age, particularly significant for Vδ1 cells. Terminally differentiated T subsets (TEMRA) were significantly increased in Vδ1 but not in Vδ2, with higher values observed in the oldest centenarians, although a great heterogeneity was observed. Both naïve and TEMRA Vδ1 and CD8+ Tαß cell values from our previous study correlated highly significantly, which was not the case for CD4+ and Vδ2. Our findings on γδ TEMRA suggest that these changes are not unfavourable for centenarians, including the oldest ones, supporting the hypothesis that immune ageing should be considered as a differential adaptation rather than a general immune alteration. The increase in TEMRA Vδ1 and CD8+, as well as in NK, would represent immune mechanisms by which the oldest centenarians successfully adapt to a history of insults and achieve longevity.

Sex and gender affect immune aging.

The proposed review aims to elucidate the intricate interplay between biological factors (sex differences) and socially constructed factors (gender differences) in the context of immune aging. While the influence of biological differences between men and women on various aspects of immune responses has long been recognized, it is crucial to acknowledge that gender, encompassing the social and cultural roles and expectations associated with being male or female, also significantly shapes these processes. Gender can either accelerate immune aging or promote longevity. By recognizing the impact of both biological and social factors, this work seeks to offer a comprehensive understanding of why men and women may experience divergent trajectories in immune aging and varying outcomes in terms of longevity. Discrepancies in perceived roles of the sexes, both within families and at work, contribute to differing patterns of antigen exposure. Additionally, variations in micronutrient intake and access to preventive healthcare facilities may exist. Health promotion knowledge often correlates with educational attainment, which is unequally represented between males and females in many cultures and across generations in the Western world. In countries without a universal healthcare system, access to healthcare relies on family prioritization strategies to cope with economic constraints, potentially limiting access to specific treatments and affecting immune responses negatively. As a result, both biological factors and social and behavioral factors associated with gender contribute to disparities in immune responses, susceptibility to infections, autoimmune diseases, and vaccine responses among older individuals. However, as demonstrated by the COVID-19 pandemic, older females exhibit greater resilience to infections than older males. Given the crucial role of the immune system in achieving longevity, it is not surprising that women live longer than men, and the number of female centenarians surpasses that of male centenarians.

The Phenotypic Characterization of the Oldest Italian Man from December 28, 2020, to September 23, 2021, A.T., Strengthens the Idea That the Immune System can Play a Key Role in the Attainment of Extreme Longevity.

In this paper, we present demographic, clinical, anamnestic, cognitive, and functional data, as well as haematological, haematochemical, immunological, and genetic parameters of an exceptional individual: A.T., a semi-supercentenarian who held the title of the oldest living Italian male centenarian from 28 December 2020, to 23 September 2021. The purpose of this study is to provide fresh insights into extreme phenotypes, with a particular focus on immune-inflammatory parameters. To the best of our knowledge, this study represents the first phenotypic investigation of a semi-supercentenarian, illustrating both INFLA-score, a metric designed to assess the cumulative impact of inflammatory markers and indicators of age-related immune phenotype (ARIP), recognized as significant gauges of biological ageing. The aim of this study was, indeed, to advance our understanding of the role of immune-inflammatory responses in achieving extreme longevity. The results of laboratory tests, as well as clinical history and interview data, when compared to the results of our recent study on Sicilian centenarians, demonstrate an excellent state of health considering his age. Consistent with previous studies, we observed increased IL-6 inflammatory markers and INFLA score in A.T. More interestingly, the semi-supercentenarian showed values of ARIP indicators such as naïve CD4+ cells, CD4+/CD8+ ratio, and CD4+TN/TM ratio in the range of young adult individuals, suggesting that his immune system's biological age was younger than the chronological one. The results support the notion that the immune system can play a role in promoting extreme longevity. However, this does not rule out the involvement of other body systems or organs in achieving extreme longevity.

Sicilian Semi- and Supercentenarians: Age-related NK Cell Immunophenotype and Longevity Trait Definition.

The immune system of semi- and supercentenarians (i.e., the oldest centenarians) is believed to have peculiar characteristics that enable them to reach extreme longevity in a relatively healthy state. Therefore, in previous papers, we investigated, through flow cytometry, variations in the percentages of the main subsets of Tαß and Tγδ cells in a Sicilian cohort of 28 women and 26 men (age range 19-110 years), including 11 long-living individuals (>90 years old) and 8 oldest centenarians. These investigations suggested that some observed immunophenotypic changes may contribute to the extreme longevity of the oldest centenarians. In the present study, to further characterize the immunophenotype of the oldest centenarians, we examined the percentages of Natural Killer (NK) cells identified as CD3-CD56 + CD16+ in the previously described Sicilian cohort. We found a highly significant increase in NK cell percentages with age. When stratified by gender, this significant increase with age was maintained in both sexes, with higher significance observed in males. Our findings on NK cells, together with the previously obtained results, discussed in the context of the literature, suggest that these changes are not unfavourable for centenarians, including the oldest ones, supporting the hypothesis that immune aging should be considered as a differential adaptation rather than a general immune alteration. These adapted immune mechanisms allow the oldest centenarians to successfully adapt to a history of insults and achieve remarkable longevity.

Special Issue "Centenarians-A Model to Study the Molecular Basis of Lifespan and Healthspan 2.0".

The global population is experiencing an increase in ageing and life expectancy [...].

Sicilian semi- and supercentenarians: identification of age-related T-cell immunophenotype to define longevity trait.

The immunophenotype of oldest centenarians, i.e. semi- and supercentenarians, could provide important information about their ability to adapt to factors associated with immune changes, including ageing per se and chronic Cytomegalovirus infection. We investigated, by flow cytometry, variations in percentages and absolute numbers of immune cell subsets, focusing on T cells, and pro-inflammatory parameters in a cohort of 28 women and 26 men (age range 19-110 years). We observed variability in hallmarks of immunosenescence related to age and Cytomegalovirus serological status. The eight oldest centenarians showed the lowest percentages of naïve T cells, due to their age, and the highest percentages of T-effector memory cells re-expressing CD45RA (TEMRA), according to their cytomegalovirus status, and high levels of serum pro-inflammatory parameters, although their means were lower than that of remaining 90+ donors. Some of them showed CD8 naïve and TEMRA percentages, and exhaustion/pro-inflammatory markers comparable to the younger ones. Our study supports the suggestion that immune ageing, especially of oldest centenarians, exhibits great variability that is not only attributable to a single contributor but should also be the full result of a combination of several factors. Everyone ages differently because he/she is unique in genetics and experience of life and this applies even more to the immune system; everybody has had a different immunological history. Furthermore, our findings on inflammatory markers, TEMRA and CMV seropositivity in centenarians, discussed in the light of the most recent literature, suggest that these changes might be not unfavourable for centenarians, and in particular for the oldest ones.

Anti-Inflammatory Effects of Nutritionally Relevant Concentrations of Oleuropein and Hydroxytyrosol on Peripheral Blood Mononuclear Cells: An Age-Related Analysis.

Immunosenescence and inflammaging facilitate the insurgence of chronic diseases. The Mediterranean diet is a non-invasive intervention to improve the chronic low-grade inflammatory status associated with aging. Olive oil oleuropein (OLE) and hydroxytyrosol (HT) demonstrated a controversial modulatory action on inflammation in vitro when tested at concentrations exceeding those detectable in human plasma. We studied the potential anti-inflammatory effects of OLE and HT at nutritionally relevant concentrations on peripheral blood mononuclear cells (PBMCs) as regards cell viability, frequency of leukocyte subsets, and cytokine release, performing an age-focused analysis on two groups of subjects: Adult (age 18-64 years) and Senior (age ≥ 65 years). OLE and HT were used alone or as a pre-treatment before challenging PBMCs with lipopolysaccharide (LPS). Both polyphenols had no effect on cell viability irrespective of LPS, but 5 µM HT had an LPS-like effect on monocytes, reducing the intermediate subset in Adult subjects. OLE and HT had no effect on LPS-triggered release of TNF-α, IL-6 and IL-8, but 5 µM HT reduced IL-10 secretion by PBMCs from Adult vs. Senior group. In summary, nutritionally relevant concentrations of OLE and HT elicit no anti-inflammatory effect and influence the frequency of immune cell subsets with age-related different outcomes.

Aging and chronic inflammation: highlights from a multidisciplinary workshop.

Aging is a gradual, continuous series of natural changes in biological, physiological, immunological, environmental, psychological, behavioral, and social processes. Aging entails changes in the immune system characterized by a decrease in thymic output of naïve lymphocytes, an accumulated chronic antigenic stress notably caused by chronic infections such as cytomegalovirus (CMV), and immune cell senescence with acquisition of an inflammatory senescence-associated secretory phenotype (SASP). For this reason, and due to the SASP originating from other tissues, aging is commonly accompanied by low-grade chronic inflammation, termed "inflammaging". After decades of accumulating evidence regarding age-related processes and chronic inflammation, the domain now appears mature enough to allow an integrative reinterpretation of old data. Here, we provide an overview of the topics discussed in a recent workshop "Aging and Chronic Inflammation" to which many of the major players in the field contributed. We highlight advances in systematic measurement and interpretation of biological markers of aging, as well as their implications for human health and longevity and the interventions that can be envisaged to maintain or improve immune function in older people.

The Nutraceutical Properties of Rhus coriaria Linn: Potential Application on Human Health and Aging Biomedicine.

Rhus coriaria Linn is a little plant growing in the Mediterranean basin, including Sicily, where it is known as Sicilian Sumac. Since antiquity, it has been used as a medicinal herb, considering its pharmacological properties and its recognized anti-inflammatory, antioxidant, and antimicrobial effects. Multiple studies have highlighted that the beneficial properties of Sumac extracts depend on the abundance of phytochemicals such as polyphenols, fatty acids, minerals, and fibers. Despite its wide use as a spice, the literature on Sumac effects on humans' health and aging is still scarce. Considering its great nutraceutical potential, Sumac could be used to treat age-related diseases such as those in which the inflammatory process plays a crucial role in manifestation and progression. Thus, Sumac could be an interesting new insight in the biomedical field, especially in aging biomedicine.

Feasibility of Ultra-Low Volume Contrast-Saline Mixture Injection With Dual-Flow Technique in a Pre-TAVI Computed Tomography Angiography.

BACKGROUND: To explore the feasibility and image quality of ultra-low volume contrast-saline mixture injection with dual-flow injection technique in a computed tomography angiography (CTA) protocol in patients scheduled for transcatheter aortic valve implantation (TAVI). METHODS: Forty (40) TAVI candidates underwent investigation with CTA using a third-generation dual-source CT scanner between September and November 2020. Different volumes of a monophasic contrast-saline mixture at an 80:20 ratio were administered at an infusion rate of 3 mL/s in 20 patients (group A). The injected volume was based on patient body mass index (BMI): 50 mL if BMI <29 kg/m2 and 63 mL if BMI >29 kg/m2. The other 20 patients (group B)-the control cases-received a total of 65 mL of contrast medium (CM), in multiphasic injections at different flow rates, followed by 10 mL of saline. The images that were obtained were prospectively evaluated for image quality, vessel attenuation (HU), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and estimated radiation dose. RESULTS: Image quality of the aortic root and ilio-femoral vessels was diagnostic in all patients. Vascular attenuation was >200 HU and CNR >3 at any vessel level. CONCLUSIONS: Data from this study suggest that a monophasic ultra-low volume contrast-saline mixture injection with a dual-flow technique can provide clear visualisation of the aortic root and ilio-femoral vessels in pre-TAVI CTA, which is comparable with a standard multiphasic volume injection protocol.

Role of Sex and Age in Fatal Outcomes of COVID-19: Women and Older Centenarians Are More Resilient.

In the present paper, we have analysed the role of age and sex in the fatal outcome of COVID-19, as there are conflicting results in the literature. As such, we have answered three controversial questions regarding this aspect of the COVID-19 pandemic: (1) Have women been more resilient than men? (2) Did centenarians die less than the remaining older people? (3) Were older centenarians more resistant to SARS-CoV-2 than younger centenarians? The literature review demonstrated that: (1) it is women who are more resilient, in agreement with data showing that women live longer than men even during severe famines and epidemics; however, there are conflicting data regarding centenarian men; (2) centenarians overall did not die less than remaining older people, likely linked to their frailty; (3) in the first pandemic wave of 2020, centenarians > 101 years old (i.e., born before 1919), but not "younger centenarians", have been more resilient to COVID-19 and this may be related to the 1918 Spanish flu epidemic, although it is unclear what the mechanisms might be involved.

Age-associated changes in circulatory fatty acids: new insights on adults and long-lived individuals.

Long-lived individuals (LLIs) are considered an ideal model to study healthy human aging. Blood fatty acid (FA) profile of a cohort of LLIs (90-111 years old, n = 49) from Sicily was compared to adults (18-64 years old, n = 69) and older adults (65-89 years old, n = 54) from the same area. Genetic variants in key enzymes related to FA biosynthesis and metabolism were also genotyped to investigate a potential genetic predisposition in determining the FA profile. Gas chromatography was employed to determine the FA profile, and genotyping was performed using high-resolution melt (HRM) analysis. Blood levels of total polyunsaturated FA (PUFA) and total trans-FA decreased with age, while the levels of saturated FA (SFA) remained unchanged. Interestingly, distinctively higher circulatory levels of monounsaturated FA (MUFA) in LLIs compared to adults and older adults were observed. In addition, among LLIs, rs174537 in the FA desaturase 1/2 (FADS1/2) gene was associated with linoleic acid (LA, 18:2n-6) and docosatetraenoic acid (DTA, 22:4n-6) levels, and the rs953413 in the elongase of very long FA 2 (ELOVL2) was associated with DTA levels. We further observed that rs174579 and rs174626 genotypes in FADS1/2 significantly affect delta-6 desaturase (D6D) activity. In conclusion, our results suggest that the LLIs have a different FA profile characterized by high MUFA content, which indicates reduced peroxidation while maintaining membrane fluidity.

Centenarians born before 1919 are resistant to COVID-19.

Although mortality from COVID-19 progressively increases with age, there are controversial data in the literature on the probability of centenarians dying from COVID-19. Moreover, it has been claimed that men in their 90s and 100s are more resilient than women. To gain insight into this matter, we analysed, according to gender, mortality data during the first year of pandemic of Sicilian nonagenarians and centenarians. We used mortality data from the 2019 as a control. The crude excess mortality between the two years was calculated. Data on deaths of Sicilian 90 + years show that, in line with what is known about the different response to infections between the two genders, oldest females are more resilient to COVID-19 than males. Moreover, centenarians born before 1919, but not "younger centenarians", are resilient to COVID-19. This latter datum should be related to the 1918 Spanish flu epidemic, although the mechanisms involved are not clear.

Distribution of KIR Genes and Their HLA Ligands in Different Viral Infectious Diseases: Frequency Study in Sicilian Population.

Natural killer (NK) cells play a role in defence against viral infections by killing infected cells or by producing cytokines and interacting with adaptive immune cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation of NK cells through their interaction with human leucocyte antigens (HLA). Ninety-six Sicilian patients positive to Human Immunodeficiency Virus-1 (HIV) and ninety-two Sicilian patients positive to SARS-CoV-2 were genotyped for KIRs and their HLA ligands. We also included fifty-six Sicilian patients with chronic hepatitis B (CHB) already recruited in our previous study. The aim of this study was to compare the distribution of KIR-HLA genes/groups of these three different infected populations with healthy Sicilian donors from the literature. We showed that the inhibitory KIR3DL1 gene and the KIR3DL1/HLA-B Bw4 pairing were more prevalent in individual CHB. At the same time, the frequency of HLA-C2 was increased in CHB compared to other groups. In contrast, the HLA-C1 ligand seems to have no contribution to CHB progression whereas it was significantly higher in COVID-19 and HIV-positive than healthy controls. These results suggest that specific KIR-HLA combinations can predict the outcome/susceptibility of these viral infections and allows to plan successful customized therapeutic strategies.

Lessons from Sicilian Centenarians for Anti-Ageing Medicine. The Oxi-Inflammatory Status.

Population ageing is a great achievement of humanity, but it also represents a challenge that the Western world is currently facing, as ageing is associated with increased susceptibility to age-related inflammatory diseases. Therefore, it is necessary to fully understand the mechanisms of healthy ageing to prevent the harmful aspects of ageing. The study of long living individuals (LLIs) is a great model for trying to achieve this goal. Accordingly, the oxy-inflammatory status of Sicilian LLIs was reviewed in the present paper. Based on the reported data, anti-inflammatory and anti-oxidative stress strategies have been discussed, useful for delaying or avoiding the onset of age-related diseases, thus favouring a healthy ageing process.

How Can We Improve the Vaccination Response in Older People? Part II: Targeting Immunosenescence of Adaptive Immunity Cells.

The number of people that are 65 years old or older has been increasing due to the improvement in medicine and public health. However, this trend is not accompanied by an increase in quality of life, and this population is vulnerable to most illnesses, especially to infectious diseases. Vaccination is the best strategy to prevent this fact, but older people present a less efficient response, as their immune system is weaker due mainly to a phenomenon known as immunosenescence. The adaptive immune system is constituted by two types of lymphocytes, T and B cells, and the function and fitness of these cell populations are affected during ageing. Here, we review the impact of ageing on T and B cells and discuss the approaches that have been described or proposed to modulate and reverse the decline of the ageing adaptive immune system.