Biogerontology

Influenza is an important cause of morbidity and mortality in the elderly and influenza vaccination has shown a decreased efficacy in aged people. Both γδ- and αβ-T cell responses, which are believed to play an important role in controlling influenza infection, are impaired during aging. The aim of this study was to evaluate the ability of influenza vaccine to induce cellular immune responses mediated by γδ- and αβ-T cells␣in healthy elderly subjects. After influenza vaccination, an increased proportion of Vγ9Vδ2 T cells having reduced proliferative capacity and increased perforin production, and then a differentiated effector/memory phenotype, was present. The peripheral number and the cytokine production of γδ T cells were not changed. A significant decrease of CD4 and CD8 naïve T cells and a corresponding increase of CD4 and CD8 memory T cells were found. The in vitro stimulation of PBMCs from elderly subjects with influenza antigens increased their proliferative capacity and the production of both IFNγ and IL-4. The vaccine was clinically effective, since in the outbreak period, only one influenza case was noted. The results reported in this study demonstrate the activation of both γδ- and αβ-T cell responses in healthy elderly after influenza vaccination.

Immunological aging is strongly associated with the observable deleterious effects of human aging. Our understanding of the causes, effects, and therapeutics of aging immune cells has long been considered within the sole purview of immunosenescence. However, it is being progressively realized that immunosenescence may not be the only determinant of immunological aging. The cellular senescence-centric theory of aging proposes a more fundamental and specific role of immune cells in regulating senescent cell (SC) burden in aging tissues that has augmented the notion of senescence immunotherapy. Now, in addition, several emerging studies are suggesting that cellular senescence itself may be prevalent in aging immune cells, and that senescent immune cells exhibiting characteristic markers of cellular senescence, similar to non-leucocyte cells, could be among the key drivers of various facets of physiological aging. The present review integrates the current knowledge related to immunosenescence and cellular senescence in immune cells per se, and aims at providing a cohesive overview of these two phenomena and their significance in immunity and aging. We present evidence and rationalize that understanding the extent and impact of cellular senescence in immune cells vis-à-vis immunosenescence is necessary for truly comprehending the notion of an ‘aged immune cell’. In addition, we also discuss the emerging significance of dietary factors such as phytochemicals, probiotic bacteria, fatty acids, and micronutrients as possible modulators of immunosenescence and cellular senescence. Evidence and opportunities related to nutritional bioactive components and immunological aging have been deliberated to augment potential nutrition-oriented immunotherapy during aging.

Invariant natural killer T (iNKT) cells represent a well-established T cell lineage characterised in humans by TCR consisting of an invariant alpha chain encoded by Vα24-JαQ genes, paired preferentially with a Vβ11 chain. iNKT cells also share some characteristics with NK cells, such as the expression of the NK-associated receptor CD161 in humans. The T cell immune response is the most dramatically affected by ageing, although age-associated alterations in the phenotype and function of other cells of the immune system have been demonstrated. Despite the importance of iNKT cells in the regulation of the immune response, there are a limited number of studies on the effect of ageing on peripheral blood iNKT cells. Thus, in this work we analyse the effect of ageing on peripheral blood Vα24+Vβ11+ iNKT cells by studying their frequency, phenotype and proliferative function in elderly individuals fulfilling the SENIEUR criteria of healthy ageing compared with healthy young donors. Our results demonstrated a significant decrease of the percentage of Vα24+Vβ11+ iNKT cells in elderly donors. No significant differences were found in the expression of CD27, CD28, CD45RO, CD45RAbright, CD161, CD94 and NKG2D on iNKT cells from young and elderly individuals. Proliferation of Vα24+Vβ11+ iNKT cells in response to α-GalCer and IL2 was analysed by calculating the cumulative population doubling (PD) after 14 days of culture. The PD levels were lower in the elderly indicating that Vα24+Vβ11+ iNKT cells from healthy elderly subjects had an impaired proliferative capacity. These results indicate that ageing associates with a significant decline in the percentage and proliferative response of peripheral blood iNKT cells. Given the important immunoregulatory role of iNKT cells, these alterations in their number and function could contribute to the deleterious immune response in the elderly.

Neonatal thymus graft and thymus calf extract (TME) in vivo treatment exert similar corrective actions on different mouse age-related alterations. The aim of the present paper is to investigate whether a vegetal extract, wheat sprout extract (WESPRE), could mimic the thymus action on recovering age-related alterations and if this extract can cure an age-associated pathology, the cataract in dogs. Present experiments were carried out by using WESPRE and TME in vivo in old mice to check their ability to recover the altered DNA synthesis in hepatocyte primary cultures. Old mice treated with WESPRE and TME showed a recovery of hepatocyte DNA synthesis levels when compared with the old untreated ones. The increase of DNA and protein contents observed in aged animals is reduced by WESPRE treatments to levels observed in young mice hepatocytes. We measured also WESPRE phosphorylation activity by endogenous kinase: it was from 10 to 40 times higher with respect to wheat seeds. Old dogs were orally treated for a month and the lens opacity analysed before and after the treatment. Results showed a reduction from 25 to 40% of lens opacity. The efficacy of wheat sprouts in the recovery of age-related alterations and in treating age-associated pathologies could be due to the contemporary presence of small regulatory acid peptides, a remarkable level of highly energetic phosphoric radicals and antioxidant molecules, peculiarities that may be, to some extent, related to the aging process regulation.

As we age, there is an age-related loss in skeletal muscle mass and strength, known as sarcopenia. Sarcopenia results in a decrease in mobility and independence, as well as an increase in the risk of other morbidities and mortality. Sarcopenia is therefore a major socio-economical problem. The mechanisms behind sarcopenia are unclear and it is likely that it is a multifactorial condition with changes in numerous important mechanisms all contributing to the structural and functional deterioration. Here, we review the major proposed changes which occur in skeletal muscle during ageing and highlight evidence for changes in physical activity and nutrition as therapeutic approaches to combat age-related skeletal muscle wasting.

Studies examining how diet affects mortality risk over age typically characterise mortality using parameters such as aging rates, which condense how much and how quickly the risk of dying changes over time into a single measure. Demographers have suggested that decoupling the tempo and the magnitude of changing mortality risk may facilitate comparative analyses of mortality trajectories, but it is unclear what biologically meaningful information this approach offers. Here, we determine how the amount and ratio of protein and carbohydrate ingested by female Drosophila melanogaster affects how much mortality risk increases over a time-standardised life-course (the shape of aging) and the tempo at which animals live and die (the pace of aging). We find that pace values increased as flies consumed more carbohydrate but declined with increasing protein consumption. Shape values were independent of protein intake but were lowest in flies consuming ~90 μg of carbohydrate daily. As protein intake only affected the pace of aging, varying protein intake rescaled mortality trajectories (i.e. stretched or compressed survival curves), while varying carbohydrate consumption caused deviation from temporal rescaling (i.e. changed the topography of time-standardised survival curves), by affecting pace and shape. Clearly, the pace and shape of aging may vary independently in response to dietary manipulation. This suggests that there is the potential for pace and shape to evolve independently of one another and respond to different physiological processes. Understanding the mechanisms responsible for independent variation in pace and shape, may offer insight into the factors underlying diverse mortality trajectories.

The effectiveness of the adaptive immune system reliesupon extensive proliferation of an initially smallnumber of antigen-specific T cells. At the end of asuccessful response, the majority die by apoptosis anda small minority joins the memory cell pool. Uponre-challenge with antigen, these memory cells mustagain undergo clonal expansion in order to mediate aneffective response. Thus, T cells are subjected tomarked proliferative stress which may result in clonalexhaustion due to replicative senescence. In othersystems made up of rapidly proliferating cells (e.g. inthe gut) individual clones are identical and arereplaced at the end of their lifespan bydifferentiation from a stem cell reservoir. However,because of the unique clonal distribution of antigenreceptors on T cells, mere replacement with other Tcells is not sufficient to maintain the integrity ofthe system. Moreover, the very source of new T cellsdecreases with age (due to thymic involution).Therefore, the adaptive immune system may be uniquelysusceptible to the deleterious effects of replicativesenescence. Particularly in humans, in vivo studies ofthe behaviour of individual T-cell clones in the bodyis difficult. However, T-cell longevity, measured asproliferative capacity in terms of populationdoublings, can be usefully modelled at the clonallevel in vitro. This paper discusses the surprisinglylittle that is known about the average longevity,variation between clones, and the maximal longevity ofhuman T cells under clonal culture conditions invitro. From our own studies, we show that averagelifespan of human T cells is as little as 17 PD;however, established clones reach 35 PD on average,with maximum longevity generally in the region of 60–80 PD, regardless of the source of the cloned cells.Expression of surface molecules in general did notdiffer strikingly between young and old donors, butthe frequency of clones secreting IL-10, and theamount secreted per clone was higher in the elderlythan in the young. Conversely, the frequency of clonessecreting IL-6 and the amount secreted per clone washigher in the young.