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.

How Important Are Genes to Achieve Longevity?

Several studies on the genetics of longevity have been reviewed in this paper. The results show that, despite efforts and new technologies, only two genes, APOE and FOXO3A, involved in the protection of cardiovascular diseases, have been shown to be associated with longevity in nearly all studies. This happens because the genetic determinants of longevity are dynamic and depend on the environmental history of a given population. In fact, population-specific genes are thought to play a greater role in the attainment of longevity than those shared between different populations. Hence, it is not surprising that GWAS replicated associations of common variants with longevity have been few, if any, as these studies pool together different populations. An alternative way might be the study of long-life families. This type of approach is proving to be an ideal resource for uncovering protective alleles and associated biological signatures for healthy aging phenotypes and exceptional longevity.

The Anticancer Potential of Plant-Derived Nutraceuticals via the Modulation of Gene Expression.

Current studies show that approximately one-third of all cancer-related deaths are linked to diet and several cancer forms are preventable with balanced nutrition, due to dietary compounds being able to reverse epigenetic abnormalities. An appropriate diet in cancer patients can lead to changes in gene expression and enhance the efficacy of therapy. It has been demonstrated that nutraceuticals can act as powerful antioxidants at the cellular level as well as anticarcinogenic agents. This review is focused on the best studies on worldwide-available plant-derived nutraceuticals: curcumin, resveratrol, sulforaphane, indole-3-carbinol, quercetin, astaxanthin, epigallocatechin-3-gallate, and lycopene. These compounds have an enhanced effect on epigenetic changes such as histone modification via HDAC (histone deacetylase), HAT (histone acetyltransferase) inhibition, DNMT (DNA methyltransferase) inhibition, and non-coding RNA expression. All of these nutraceuticals are reported to positively modulate the epigenome, reducing cancer incidence. Furthermore, the current review addresses the issue of the low bioavailability of nutraceuticals and how to overcome the drawbacks related to their oral administration. Understanding the mechanisms by which nutraceuticals influence gene expression will allow their incorporation into an "epigenetic diet" that could be further capitalized on in the therapy of cancer.

Small Fiber Neuropathy in Patients with Chronic Pain and a Previous Diagnosis of Multiple Chemical Sensitivity Syndrome.

Small fiber neuropathy (SFN) is characterized by the involvement of Aδ and C fibers leading to sensory, mainly pain, and/or autonomic symptoms. Multiple chemical sensitivity syndrome (MCS) is an incompletely defined condition characterized by the onset of various symptoms in patients after exposure to several chemical substances. Pain is a common symptom in these patients. In this study, we report the histological and clinical data of a cohort of 21 patients who had been diagnosed as having MCS and who were referred to us with the suspicion of SFN because of chronic pain. All patients underwent neurological clinical examination, (including scales for pain and autonomic disorders), and a skin biopsy. Age-matched healthy subjects were used as controls for the skin biopsies. Nerve conduction studies and serum screening to exclude possible causes of peripheral neuropathy were also performed. Skin biopsies disclosed a somatic SFN in all patients. Although the majority (18 out of 21) of patients also had autonomic symptoms. we found sparing of autonomic innervation in the biopsies. These observations suggest that chronic pain in MCS could be secondary to the presence of somatic SFN, although more data are needed to confirm these observations.

The Phenotypic Characterization of the Cammalleri Sisters, an Example of Exceptional Longevity.

This article shows demographic, clinical, anamnestic, cognitive, and functional data as well as biochemical, genetic, and epigenetic parameters of two exceptional siblings: Diega (supercentenarian) and Filippa (semisupercentenarian) Cammalleri. The purpose of this study is to provide new insights into the extreme phenotypes represented by semisupercentenarians and supercentenarians. Different studies have been published on supercentenarians, but to the best of our knowledge, this is the only concerning two sisters and the most detailed from a phenotypic point of view. Our findings agree with the suggestion that supercentenarians have an increasing relative resistance to age-related diseases, approximating the limits of the functional human reserve to address successfully the acute causes of death. More interestingly, our data agree with, and extend, the suggestion that inflammation and oxidative stress predict centenarian mortality.

Genotypic and Phenotypic Aspects of Longevity: Results from a Sicilian Survey and Implication for the Prevention and Treatment of Age-related Diseases.

BACKGROUND: It is well known that long living individuals are a model of successful ageing and that the identification of both genetic variants and environmental factors that predispose to a long and healthy life is of tremendous interest for translational medicine. METHODS: We present the preliminary findings obtained from an ongoing study on longevity conducted on a sample of Sicilian long-lived individuals. RESULTS: We review the characteristics of longevity in Sicily, taking into account lifestyle, environment, genetics, hematochemical values, body composition and immunophenotype. In addition, we discuss the possible implications of our data for the prevention and/or treatment of age-related diseases. CONCLUSION: As widely discussed in this review, the explanation of the role of genetics and lifestyle in longevity can provide important information on how to develop drugs and/or behaviours that can slow down or delay ageing. Thus, it will be possible to understand, through a "positive biology" approach, how to prevent and/or reduce elderly frailty and disability.

Dietary Supplements as Surrogate of Mediterranean Diet in Healthy Smoking Subjects.

The interventions to slow aging, favoring active life expectancy, represent the new perspectives in ageing investigation. Some mechanisms that delay or prevent the onset of aging pathologies have been identified. Between them, a healthy lifestyle seems to reduce many risk factors. In particular, eating habits represent the most concrete, low-cost way to act on aging process. Mediterranean diet has received much attention since its antioxidant and anti-inflammatory effects have been consistently demonstrated. Unfortunately, many people follow a Western diet, poor in phytochemicals that represent the main source of beneficial effects of this dietary pattern. So, supplements administration should be considered, especially in subjects exposed to high level of oxidative stress and inflammation. So, we tested the properties of a commercial food supplement containing a series of plant polyphenols in combination with caffeine, bioperine (black pepper extract), and selenium in smoking healthy volunteers. Fifty participants have been recruited and hematochemical analyses and biochemistry tests have been performed, before and after 60 days of supplement intake. Thirteen subjects dropped out of the study. At the end of the intervention, the variation of inflammatory and oxidant markers has been evaluated, measuring urinary isoprostanes, serum advanced glycation end products, and oxidized low-density lipoproteins. The results showed that this supplement exhibits promising antioxidant and anti-inflammatory responses, especially in women, highlighting the role of supplementation in certain groups of subjects, for the control of oxidative stress as well as inflammatory status. So, its intake should be useful in delaying the onset of age-related diseases.