Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions : a study on postmenopausal monozygotic twin pairs

MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case-control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54-62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen's causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the act…

Menopause and adipose tissue: miR-19a-3p is sensitive to hormonal replacement

Tissue-specific effects of 17 beta-estradiol are delivered via both estrogen receptors and microRNAs (miRs). Menopause is known to affect the whole-body fat distribution in women. This investigation aimed at identifying menopause-and hormone replacement therapy (HRT)-associated miR profiles and miR targets in subcutaneous abdominal adipose tissue and serum from the same women. A discovery phase using array technology was performed in 13 women, including monozygotic twin pairs discordant for HRT and premenopausal young controls. Seven miRs, expressed in both adipose tissue and serum, were selected for validation phase in 34 women from a different cohort. An age/menopause-related increase of …

The extreme longevity: the state of the art in Italy

Age-Related Inflammation: the Contribution of Different Organs, Tissues and Systems. How to Face it for Therapeutic Approaches

A typical feature of ageing is a chronic, low-grade inflammation characterized by a general increase in the production of pro-inflammatory cytokines and inflammatory markers ("inflamm-ageing"). This status may slowly damage one or several organs, especially when unfavorable genetic polymorphisms and epigenetic alterations are concomitant, leading to an increased risk of frailty together with the onset of age-related chronic diseases. The contribution of different tissues (adipose tissue, muscle), organs (brain, liver), immune system and ecosystems (gut microbiota) to age-related inflammation ("inflamm-ageing") will be discussed in this review in the context of its onset/progression leading …

Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians

In this paper, we review data of recent literature on the distribution in centenarians of candidate germ-line polymorphisms that likely affect the individual chance to reach the extreme limit of human life. On the basis of previous observations on the immunology, endocrinology and cellular biology of centenarians we focused on genes that regulate immune responses and inflammation (IL-6, IL-1 cluster, IL-10), genes involved in the insulin/IGF-I signalling pathway and genes that counteract oxidative stress (PON1). On the whole, data indicate that polymorphisms of these genes likely contribute to human longevity, in accord with observations emerging from a variety of animal models, and suggest…

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, …

Genes, Ageing and Longevity in Humans: Problems, Advantages and Perspectives.

Many epidemiological data indicate the presence of a strong familial component of longevity that is largely determined by genetics, and a number of possible associations between longevity and allelic variants of genes have been described. A breakthrough strategy to get insight into the genetics of longevity is the study of centenarians, the best example of successful ageing. We review the main results regarding nuclear genes as well as the mitochondrial genome, focusing on the investigations performed on Italian centenarians, compared to those from other countries. These studies produced interesting results on many putative "longevity genes". Nevertheless, many discrepancies are reported, l…

Circulating miRNAs and miRNA shuttles as biomarkers: Perspective trajectories of healthy and unhealthy aging

Human aging is a lifelong process characterized by a continuous trade-off between pro-and anti-inflammatory responses, where the best-adapted and/or remodeled genetic/epigenetic profile may develop a longevity phenotype. Centenarians and their offspring represent such a phenotype and their comparison to patients with age-related diseases (ARDs) is expected to maximize the chance to unravel the genetic makeup that better associates with healthy aging trajectories. Seemingly, such comparison is expected to allow the discovery of new biomarkers of longevity together with risk factor for the most common ARDs. MicroRNAs (miRNAs) and their shuttles (extracellular vesicles in particular) are curre…

Human longevity within an evolutionary perspective: The peculiar paradigm of a postreproductive genetics

The data we collected on the genetics of human longevity, mostly resulting from studies on centenarians, indicate that: (1) centenarians and long-living sib-pairs are a good choice for the study of human longevity, because they represent an extreme phenotype, i.e., the survival tail of the population who escaped neonatal mortality, pre-antibiotic era illnesses, and fatal outcomes of age-related complex diseases. (2) The model of centenarians is not simply an additional model with respect to well-studied organisms, and the study of humans has revealed characteristics of ageing and longevity (geographical and sex differences, role of antigenic load and inflammation, role of mtDNA variants) wh…

Ageing, longevity, exceptional longevity and related genetic and non genetics markers: panel statement

In May 2012, a group of scientists and clinicians met in Athens (Greece) to consider the relevance of ageing, longevity, exceptional longevity and related genetic and non genetic markers. During this meeting, we firstly reviewed recent epidemiological and clinical studies on ageing, longevity and exceptional longevity, briefly analysed the ageing theories and discussed successful and unsuccessful ageing also taking into account the evolutionary perspective. Secondly, we considered the three phenotypes based on the definition of ageing, longevity and exceptional longevity and the associated biomarkers. Third, we discussed proposed treatments suitable to counteract or slow down ageing. Finall…

Corrigendum to “Immune parameters identify Italian centenarians with a longer five-year survival independent of their health and functional status” [Exp. Gerontol. 54C (2014) 14–20]

8 a Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy 9 b CIG—Interdepartmental Centre L. Galvani, University of Bologna, Bologna, Italy 10 c Physics and Astronomy Department, University of Bologna, Bologna, Italy 11 d Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy 12 e Immunosenescence Unit, Department of Pathobiology and Biomedical Methodologies, University of Palermo, Palermo, Italy 13 f Geriatric Unit IRCCS Ca' Granda Foundation Maggiore Policlinico Hospital, University of Milan, Italy 14 g Department of Clinical Sciences and Community Health, University of Milan, Italy 15 h Experimental Laboratory o…

Circulating miR-21, miR-146a and Fas ligand respond to postmenopausal estrogen-based hormone replacement therapy--a study with monozygotic twin pairs.

Biological aging is associated with physiological deteriorations and its’ remodeling, which are partly due to changes in the hormonal profile. MicroRNAs are known to post-transcriptionally regulate various cellular processes associated with cell senescence; differentiation, replication and apoptosis. Measured from the serum, microRNAs have the potential to serve as noninvasive markers for diagnostics/prognostics and therapeutic targets. We analysed the association of estrogen-based hormone replacement therapy (HRT) with selected microRNAs and inflammation markers from the serum, leukocytes and muscle tissue biopsy samples obtained from 54-62 year-old postmenopausal monozygotic twins (n=11 p…

Risk profiles in type 2 diabetes (metabolic syndrome): integration of IL-10 polymorphisms and laboratory parameters to identify vascular damages related complications

Recently it has been reported that low serum IL-10 levels are associated with an increased susceptibility for metabolic syndrome and type 2 diabetes mellitus (T2DM). We investigated whether the -1087G/A (rs1800896), -824C/T (rs1800871), -597C/A (rs1800872) IL-10 polymorphisms were associated with type 2 diabetes in a study on a cohort of Italian Caucasians comprising 490 type 2 diabetic and 349 control subjects. Stratifying the data according to IL-10 genotypes, trends for the progressive increase of glucose and neutrophil levels were observed in -1087GG vs. -1087GA vs. -1087AA positive diabetic patients (-1087GG < -1087GA < -1087AA). In addition, evaluating the laboratory parameters accord…

The Challenges in Moving from Ageing to Successful Longevity

During the last decades survival has significantly improved and centenarians are becoming a fast-growing group of the population. Human life span is mainly dependent on environmental and genetic factors. Favourable modifications of lifestyle factors (e.g. physical activity, diet and not smoking) and healthcare (e.g. effective vascular disease prevention) have also increased human life span. Genetic factors contribute to the variation of human life span by around 25%, which is believed to be more profound after 85 years of age. It is likely that multiple factors influence life span and we need answers to questions such as: 1) What does it take to reach 100?, 2) Do centenarians have better he…

Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-233 expressions: A study on postmenopausal monozygotic twin pairs

MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case–control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54–62- years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen’s causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the ac…