Elisa Pini

Immunosenescence and Immunogenetics of Human Longevity

At present, individuals can live up to 80–120 years, a time much longer than that of our ancestors, as a consequence of the improvements in life conditions and medical care. Thus, the human immune system has to cope with a lifelong and evolutionarily unpredicted exposure to a variety of antigens, which are at the basis of profound age-related changes globally indicated as immunosenescence, a multifaceted phenomenon that increases morbidity and mortality due to infections and age-related pathologies. The major changes occurring during immunosenescence are the result of the accumulation of cellular, molecular defects and involutive phenomena (such as thymic involution) occurring concomitantly to a hyperstimulation of both innate and adaptive immunity (accumulation of expanded clones of memory and effector T cells, shrinkage of the T cell receptor repertoire, progressive activation of macrophages), and resulting in a low-grade, chronic state of inflammation defined as inflammaging. It is unknown whether inflammaging, which represents a risk factor for most age-related pathologies, is a cause or rather an effect of the aging process. In this complex scenario, the role of genetic background likely represents a fundamental variable to attain successful aging and longevity. Accordingly, centenarians seem to be equipped with gene variants that allow them to optimize the balance between pro- and anti-inflammatory molecules, and thus to minimize the effects of the lifelong exposure to environmental insults and stressors. The remarkable features of the genetics of aging and longevity are reviewed, stressing the unexpected and unusual results obtained regarding such a postreproductive type of genetics.

Immune System, Cell Senescence, Aging and Longevity - Inflamm-Aging Reappraised

Inflamm-aging, that is the age-associated inflammatory status, is considered one of the most striking consequences of immunosenescence, as it is believed to be linked to the majority of age-associated diseases sharing an inflammatory basis. Nevertheless, evidence is emerging that inflamm-aging is at least in part independent from immunological stimuli. Moreover, centenarians who avoided or delayed major inflammatory diseases display markers of inflammation. In this paper we proposed a reappraisal of the concept of inflamm-aging, suggesting that its pathological effects can be independent from the total amount of pro-inflammatory mediators, but they would be rather associated with the anatomical district and type of cells where they are produced and where they primarily act.

Inflammaging and cancer: a challenge for the Mediterranean diet.

Aging is considered the major risk factor for cancer, one of the most important mortality causes in the western world. Inflammaging, a state of chronic, low-level systemic inflammation, is a pervasive feature of human aging. Chronic inflammation increases cancer risk and affects all cancer stages, triggering the initial genetic mutation or epigenetic mechanism, promoting cancer initiation, progression and metastatic diffusion. Thus, inflammaging is a strong candidate to connect age and cancer. A corollary of this hypothesis is that interventions aiming to decrease inflammaging should protect against cancer, as well as most/all age-related diseases. Epidemiological data are concordant in suggesting that the Mediterranean Diet (MD) decreases the risk of a variety of cancers but the underpinning mechanism(s) is (are) still unclear. Here we review data indicating that the MD (as a whole diet or single bioactive nutrients typical of the MD) modulates multiple interconnected processes involved in carcinogenesis and inflammatory response such as free radical production, NF-κB activation and expression of inflammatory mediators, and the eicosanoids pathway. Particular attention is devoted to the capability of MD to affect the balance between pro- and anti-inflammaging as well as to emerging topics such as maintenance of gut microbiota (GM) homeostasis and epigenetic modulation of oncogenesis through specific microRNAs.

Reprint of: A parallel randomized trial on the effect of a healthful diet on inflammageing and its consequences in European elderly people: design of the NU-AGE dietary intervention study.

BACKGROUND The proportion of European elderly is expected to increase to 30% in 2060. Combining dietary components may modulate many processes involved in ageing. So, it is likely that a healthful diet approach might have greater favourable impact on age-related decline than individual dietary components. This paper describes the design of a healthful diet intervention on inflammageing and its consequences in the elderly. METHODS The NU-AGE study is a parallel randomized one-year trial in 1250 apparently healthy, independently living European participants aged 65-80 years. Participants are randomised into either the diet group or control group. Participants in the diet group received dietary advice aimed at meeting the nutritional requirements of the ageing population. Special attention was paid to nutrients that may be inadequate or limiting in diets of elderly, such as vitamin D, vitamin B12, and calcium. C-reactive protein is measured as primary outcome. DISCUSSION The NU-AGE study is the first dietary intervention investigating the effect of a healthful diet providing targeted nutritional recommendations for optimal health and quality of life in apparently healthy European elderly. Results of this intervention will provide evidence on the effect of a healthful diet on the prevention of age related decline.

Immune parameters identify Italian centenarians with a longer five-year survival independent of their health and functional status

Centenarians are rare and exceptional individuals characterized by a peculiar phenotype. They are the best example of healthy aging in humans as most of them have escaped or substantially delayed the onset of major age-related diseases. Within this scenario, the purpose of the present work was to understand if immune status is associated with survival and health status in centenarians. To this aim, 116 centenarians were concomitantly characterized for their immunological, health and functional status, and followed-up for five-year survival. On the basis of previous knowledge we focused on a core of fundamental and basic immune parameters (number of leukocytes, monocytes, total lymphocytes, CD3(+) T lymphocytes, CD4(+) helper T lymphocytes, CD8(+) cytotoxic T lymphocytes, CD19(+) B lymphocytes and plasma levels of IgM), and the most important findings can be summarized as follows: i. a hierarchical cluster analysis was able to define Cluster1 (88 centenarians) and Cluster2 (28 centenarians) characterized by low and high values of all these immune parameters, respectively; ii. centenarians of Cluster2 showed a statistically longer five-year survival and more favorable values of other important immune (naïve, activated/memory and effector/memory T cells) and metabolic (glycemia, insulin and HOMA-IR) parameters, in accord with previous observations that centenarians have a peculiar immune profile, a preserved insulin pathway and a lower incidence of type 2 diabetes; and iii. unexpectedly, parameters related to frailty, as well as functional and cognitive status, did not show any significant correlation with the immune clustering, despite being capable per se of predicting survival. In conclusion, high values of basic immunological parameters and important T cell subsets correlate with five-year survival in centenarians, independent of other phenotypic characteristics. This unexpected biological scenario is compatible with the general hypothesis that in centenarians a progressive disconnection and loss of biological coherence among the different functions of the body occur, where survival/mortality result from the failure of any of these domains which apparently follow an independent age-related trajectory.

Metabolic syndrome in the offspring of centenarians: focus on prevalence, components, and adipokines.

With aging, an increased prevalence of a clustering of metabolic abnormalities has been observed. These abnormalities include obesity, dyslipidemia, hypertension, and insulin resistance and are collectively known as metabolic syndrome (MetS), a low-grade, systemic, inflammatory condition associated with an increased risk of cardiovascular disease, diabetes, and other adverse health outcomes. A number of studies have demonstrated that centenarians’ offspring have a significant survival advantage and a lower risk of developing the most important age-related diseases. They therefore represent one of the best models with which to study the familiar component of human longevity. The aim of this study was to determine if the offspring of centenarians (n = 265 subjects) showed a different prevalence of MetS in comparison to the offspring of non-long-lived parents (controls, n = 101 subjects). In addition, we assessed whether centenarians’ offspring showed particular features of MetS and a distinct regulation of circulating adipokines, cytokines, and metabolic mediators. Although the prevalence of MetS was quite similar both in the offspring of centenarians and the controls, MetS-affected centenarians’ offspring seemed healthier, more functionally fit, and had lower resistin levels. MetS prevalence did not change in centenarians’ offspring across resistin, IGF-1, and resistin/IGF-1 ratio tertiles. On the other hand, in controls, MetS prevalence strongly increased across resistin tertiles and in the third resistin/IGF-1 ratio tertile, indicating a dramatic increase in MetS prevalence when the ratio between these two factors is unbalanced, with high levels of resistin and low levels of IGF-1.

Centenarians’ offspring as a model of healthy aging: a reappraisal of the data on Italian subjects and a comprehensive overview

Within the scenario of an increasing life expectancy worldwide it is mandatory to identify determinants of healthy aging. Centenarian offspring (CO) is one of the most informative model to identify trajectories of healthy aging and their determinants (genetic and environmental), being representative of elderly in their 70th whose lifestyle can be still modified to attain a better health. This study is the first comprehensive investigation of the health status of 267 CO (mean age: 70.2 years) and adopts the innovative approach of comparing CO with 107 age-matched offspring of non-long-lived parents (hereafter indicated as NCO controls), recruited according to strict inclusion demographic criteria of Italian population. We adopted a multidimensional approach which integrates functional and cognitive assessment together with epidemiological and clinical data, including pro- and anti-inflammatory cytokines and adipokines, lipid profile, and insulin resistance. CO have a lower prevalence of stroke, cerebral thrombosis-hemorrhage, hypertension, hypercholesterolemia, and other minor diseases, lower BMI and waist circumference, a better functional and cognitive status and lower plasma level of FT4 compared to NCO controls. We conclude that a multidimensional approach is a reliable strategy to identify the health status of elderly at an age when interventions to modify their health trajectory are feasible.

MARK-AGE population: From the human model to new insights

iriam Capria,b,∗,1, María Moreno-Villanuevac,1, Elisa Ceveninia, Elisa Pinia, aria Scurti a, Vincenzo Borelli a, Maria Giustina Palmasb, Marco Zolid, Christiane Schöne, nne Siepelmeyere, Jürgen Bernhardte, Simone Fiegl f, Gerben Zondagg, nton J.M. de Craenh, Antti Hervoneni, Mikko Hurmei, Ewa Sikora j, Efstathios S. Gonosk, onstantinos Voutetakisk, Olivier Toussaint l, Florence Debacq-Chainiauxl, eatrix Grubeck-Loebensteinm, Alexander Bürklec, Claudio Franceschia,b

Memofilm Project: “Man's Memory. Cinema Against the Pathologies of Memory”

To the Editor: According to “The Role of Energetic Cost in the Age-Related Slowing of Gait Speed,” walking is essential to a person’s daily life because it is required when performing different activities, but older individuals often walk more slowly because of poor fitness or health. The purpose of this study was to conclude whether it is a compensation approach of older individuals to lower their energetic expenditure cost by walking slowly. This study was conducted using 420 participants with a mean age of 68.1. To find energy expenditure, which was measured per minute and per meter, a 2.5-minute walking course was set up where participants would walk at their usual speed over 6 m. The average usual gait speed was 1.1 m/s, although the study found that usual gait speed was slower in individuals aged 65 and older. The study also found that, as age increased, so did the energy expenditure per meter walked. When graphed, energy expenditure sloped upward between the ages of 65 and 80, and the slope was even steeper after the age of 80. Results “suggest that older persons may slow down to minimize energy expenditure in the face of age-related inefficiencies that cause the cost of walking per meter to rise exponentially.” The results of this study may be used in evidencebased practice. If it is determined that older individuals have decreased their gait speed since they have become older, it may be an indicator of another problem. In this study, comorbid ailments found in participants included heart disease, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, diabetes mellitus, and osteoarthritis. It was concluded through the findings that such conditions play a significant role in slowing gait speed. These findings should result in a physician looking closely at possible ailments if it is determined that an individual’s gait speed has decreased over the years, because there could be an underlying cause. Some limitations were discussed in this study. Before the study was conducted, participants were required to undergo a health screening to determine whether they could participate in the study. As a result, some individuals who were not healthy enough could not participate in the study. Only participants who were healthier than the general population participated in the study. Also, there is no way to determine whether the participants were walking at a constant pace during the 2.5 minutes they were being examined. This study was conducted as a crosssectional study and might benefit more from a longitudinal study being performed. Other limitations that were not discussed in this article include using participants from a single geographical area, because some conditions may be more prevalent in certain areas, and not using participants of different ethnicities. One study used Brazilian subjects to compare the gait speeds of different ages. The results of this study were similar in that the gait speeds of the participants aged 70 and older were significantly slower than in their younger counterparts. It was evident that gait speed had an age-related decline in this study as well. This research could be extended by performing a longitudinal study that includes participants of different ethnicities and from different geographical locations. The variations in the participants would add validity to the findings that this study would produce. There is also evidence that a change in gait speed increases the risk of falls in elderly individuals. A study to further test and validate this greater risk is necessary. Adding the implication of variation within participants would result in significant findings. “Loss of mobility with age poses a substantive threat to life quality and seriously impacts the capacity to live independently. Slow or slowing gait speed frequently precedes mobility limitations and disability.” The information provided from this study should be used in the future of health care. Because of the evidence that slowing gait speed may be a result of another health condition, physicians should be aware that patients might need further examination for other health problems. It is important to stop the slowing of gait speed because it could result in a loss of mobility and therefore a loss of independence for elderly individuals, as well as increasing their risk of falls. It is of great importance to future studies to determine how to delay or improve gait speed.