Circulating miR-181a as a novel potential plasma biomarker for multimorbidity burden in the older population.

BACKGROUND: Chronic low-level inflammation is thought to play a role in many age-related diseases and to contribute to multimorbidity and to the disability related to this condition. In this framework, inflamma-miRs, an important subset of miRNA able to regulate inflammation molecules, appear to be key players. This study aimed to evaluate plasma levels of the inflamma-miR-181a in relation to age, parameters of health status (clinical, physical, and cognitive) and indices of multimorbidity in a cohort of 244 subjects aged 65- 97. METHODS: MiR-181a was isolated from plasma according to standardized procedures and its expression levels measured by qPCR. Correlation tests and multivariate regression analyses were applied on gender-stratified groups. RESULTS: MiR-181a levels resulted increased in old men, and significantly correlated with worsened blood parameters of inflammation (such as low levels of albumin and bilirubin and high lymphocyte content), particularly in females. Furthermore, we found miR-181a positively correlated with the overall multimorbidity burden, measured by CIRS Comorbidity Score, in both genders. CONCLUSIONS: These data support a role of miR-181a in age-related chronic inflammation and in the development of multimorbidity in older adults and indicate that the routes by which this miRNA influence health status are likely to be gender specific. Based on our results, we suggest that miR-181a is a promising biomarker of health status of the older population.

Amino acids and amino acid sensing: implication for aging and diseases.

Biogerontological research indicates nutrition as one of the major determinants of healthy aging, due to the role of nutrients in maintaining the dynamic-homeostasis of the organism. In this frame, the importance of proteins and constitutive amino acids (AAs), and in particular of functional AAs is emerging. The ability to sense and respond to changes in AAs availability is mediated by a complex network of dynamic players, crucial for an efficient regulation of their downstream effects. Here, we reviewed the current knowledge about the involvement of AA sensing mechanisms in aging and age-related diseases, focusing our attention on mTORC1 and AA transporters. In this context it is of note that alterations in AA sensors have been reported to be directly implicated in age-related phenotypes, suggesting that their modulation can represent a possible strategy for modulating (and possibly delaying) aging decline. Furthermore, these alterations may influence the effects of AA supplementation, by influencing the individual answer to AA availability. On the whole, evidences support the hypothesis that the efficiency of components of AA sensing network may have important implications for therapy, and their knowledge may be crucial for programming AA supplementation for contrasting age-related phenotypes, opening new opportunities for therapeutic interventions aimed to promote human health span.

Contribution of polymorphic variation of inositol hexakisphosphate kinase 3 (IP6K3) gene promoter to the susceptibility to late onset Alzheimer's disease.

Maintenance of electric potential and synaptic transmission are energetically demanding tasks that neuronal metabolism must continually satisfy. Inability to fulfil these energy requirements leads to the development of neurodegenerative disorders, including Alzheimer's disease. A prominent feature of Alzheimer's disease is in fact neuronal glucose hypometabolism. Thus understanding the fine control of energetic metabolism might help to understand neurodegenerative disorders. Recent research has indicated that a novel class of signalling molecules, the inositol pyrophosphates, act as energy sensors. They are able to alter the balance between mitochondrial oxidative phosphorylation and glycolytic flux, ultimately affecting the cellular level of ATP. The neuronal inositol pyrophosphate synthesis relies on the activity of the neuron enriched inositol hexakisphosphate kinase 3 (IP6K3) enzyme. To verify an involvement of inositol pyrophosphate signalling in neurodegenerative disorders, we performed tagging single nucleotide polymorphism (SNP) analysis of the IP6K3 gene in patients with familial and sporadic late onset Alzheimer's disease (LOAD). Two SNPs in the 5'-flanking promoter region of the IP6K3 gene were found to be associated with sporadic LOAD. Characterizing the functionality of the two polymorphisms by luciferase assay revealed that one of them (rs28607030) affects IP6K3 promoter activity, with the G allele showing an increased activity. As the same allele has a beneficial effect on disease risk, this may be related to upregulation of IP6K3 expression, with a consequent increase in inositol pyrophosphate synthesis. In conclusion, we provide the first evidence for a contribution of genetic variability in the IP6K3 gene to LOAD pathogenesis.

Pleiotropic effects of UCP2-UCP3 variability on leucocyte telomere length and glucose homeostasis.

The rate of telomere-shortening has been widely reported as a marker of risk for age-related conditions and mortality in human population. Genetic, environmental and stochastic factors have been shown to influence telomere attrition. In particular oxidative stress has been reported to play an important role on the process. Uncoupling proteins (UCPs) are among the most important regulators of cellular metabolism and oxidative stress. Several authors investigated the association of UCP genetic variants with leucocyte telomere length (LTL) in both healthy and unhealthy (affected by diabetes) subjects, reporting contrasting results. We tested the influence of four SNPs falling in UCP2-UCP3 genomic region on LTL and glucose metabolism by analyzing these polymorphisms in a cohort of 457 subjects, in an age range 64-105 years. Among subjects younger than 85 years, homozygotes for the minor alleles at two UCP2 variants (rs659366-A and rs660339-T) showed shorter LTL respect to the other genotypes (pmodel = 0.024). In the same samples, AA-rs659366 genotype was found associated with lower haematological levels of Glycosylate Haemoglobyn (p = 0.012 and p = 0.022, respectively). Furthermore, rs659366-AA at UCP2 and rs15673-TT at UCP3 were correlated to diabetes in a small sub-group of patients. Results here presented suggest that UCP variability has different pleiotropic effects, by affecting both telomere length and glucose homeostasis, likely through an influence on energy metabolism and stress response.

Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.

The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Population-specific association of genes for telomere-associated proteins with longevity in an Italian population.

Leukocyte telomere length (LTL) has been observed to be hereditable and correlated with longevity. However, contrasting results have been reported in different populations on the value of LTL heritability and on how biology of telomeres influences longevity. We investigated whether the variability of genes correlated to telomere maintenance is associated with telomere length and affects longevity in a population from Southern Italy (20-106 years). For this purpose we analyzed thirty-one polymorphisms in eight telomerase-associated genes of which twelve in the genes coding for the core enzyme (TERT and TERC) and the remaining in genes coding for components of the telomerase complex (TERF1, TERF2, TERF2IP, TNKS, TNKS2 and TEP1). We did not observe (after correcting for multiple testing) statistically significant associations between SNPs and LTL, possibly suggesting a low genetic influence of the variability of these genes on LTL in the elderly. On the other hand, we found that the variability of genes encoding for TERF1 and TNKS2, not directly involved in LTL, but important for keeping the integrity of the structure, shows a significant association with longevity. This suggests that the maintenance of these chromosomal structures may be critically important for preventing, or delaying, senescence and aging. Such a correlation was not observed in a population from northern Italy that we used as an independent replication set. This discrepancy is in line with previous reports regarding both the population specificity of results on telomere biology and the differences of aging in northern and southern Italy.

Evidence for a relationship between genetic polymorphisms of the L-DOPA transporter LAT2/4F2hc and risk of hypertension in the context of chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) and hypertension are chronic diseases affecting a large portion of the population frequently coexistent and interdependent. The inability to produce/use adequate renal dopamine may contribute to the development of hypertension and renal dysfunction. The heterodimeric amino acid transporter LAT2/4F2hc (SLC7A8/SLC3A2 genes) promotes the uptake of L-DOPA, the natural precursor of dopamine. We examined the plausibility that SLC7A8/SLC3A2 gene polymorphisms may contribute to hypertensive CKD by affecting the L-DOPA uptake. METHODS: 421 subjects (203 men and 218 women, mean age of 78.9 ± 9.6 years) were recruited and divided in four groups according to presence/absence of CKD, defined as reduced estimated glomerular filtration rate (eGFR < 60 ml/min/m2) calculated using the creatinine-based Berlin Initiative Study-1 (BIS1) equation, and to presence/absence of hypertension (systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg). Subjects were analysed for selected SNPs spanning the SLC7A8 and SLC3A2 loci by Sequenom MassARRAY iPLEX platform. RESULTS: The most significant SNP at the SLC3A2 (4F2hc) locus was rs2282477-T/C, with carriers of the C-allele having a lower chance to develop hypertension among CKD affected individuals [OR = 0.33 (CI 0.14-0.82); p = 0.016]. A similar association with hypertensive CKD was found for the SLC7A8 (LAT2) rs3783436-T/C, whose C-allele resulted associated with decreased risk of hypertension among subjects affected by CKD [OR = 0.56 (95% CI 0.35-0.90; p = 0.017]. The two variants were predicted to be potentially functional. CONCLUSIONS: The association between SLC3A2 and SLC7A8 variants to hypertension development in patients with renal failure could be linked to changes in L-DOPA uptake and consequently dopamine synthesis. Although the associations do not survive correction for Bonferroni multiple testing, and additional research is needed, our study opens new avenues for future basic and translational research in the field of hypertensive CKD.

Genetic variability of FOXP2 and its targets CNTNAP2 and PRNP in frontotemporal dementia: A pilot study in a southern Italian population.

The Forkhead box P2 (FOXP2) is an evolutionary conserved transcription factor involved in the maintenance of neuronal networks, implicated in language disorders. Some evidence suggests a possible link between FOXP2 genetic variability and frontotemporal dementia (FTD) pathology and related endophenotypes. To shed light on this issue, we analysed the association between single-nucleotide polymorphisms (SNPs) in FOXP2 and FTD in 113 patients and 223 healthy controls. In addition, we investigated SNPs in two putative targets of FOXP2, CNTNAP2, Contactin-associated protein-like 2 and PRNP, prion protein genes. Overall, 27 SNPs were selected by a tagging approach. FOXP2-rs17213159-C/T resulted associated with disease risk (OR = 2.16, P = 0.0004), as well as with age at onset and severity of dementia. Other FOXP2 markers were associated with semantic and phonological fluency scores, cognitive levels (MMSE) and neuropsychological tests. Associations with language, cognitive and brain atrophy measures were found with CNTNAP2 and PRNP genetic variability. Overall, although preliminary, results here presented suggest an influence of regulatory pathways centred on FOXP2 as a molecular background of FTD affecting neurological function of multiple brain areas.

Common polymorphisms in nitric oxide synthase (NOS) genes influence quality of aging and longevity in humans.

Nitric oxide (NO) triggers multiple signal transduction pathways and contributes to the control of numerous cellular functions. Previous studies have shown in model organisms that the alteration of NO production has important effects on aging and lifespan. We studied in a large sample (763 subjects, age range 19-107 years) the variability of the three human genes (NOS1, -2, -3) coding for the three isoforms of the NADPH-dependent enzymes named NO synthases (NOS) which are responsible of NO synthesis. We have then verified if the variability of these genes is associated with longevity, and with a number of geriatric parameters. We found that gene variation of NOS1 and NOS2 was associated with longevity. In addition NOS1 rs1879417 was also found to be associated with a lower cognitive performance, while NOS2 rs2297518 polymorphism showed to be associated with physical performance. Moreover, SNPs in the NOS1 and NOS3 genes were respectively associated with the presence of depression symptoms and disability, two of the main factors affecting quality of life in older individuals. On the whole, our study shows that genetic variability of NOS genes has an effect on common age related phenotypes and longevity in humans as well as previously reported for model organisms.

Exploring the role of genetic variability and lifestyle in oxidative stress response for healthy aging and longevity.

Oxidative stress is both the cause and consequence of impaired functional homeostasis characterizing human aging. The worsening efficiency of stress response with age represents a health risk and leads to the onset and accrual of major age-related diseases. In contrast, centenarians seem to have evolved conservative stress response mechanisms, probably derived from a combination of a diet rich in natural antioxidants, an active lifestyle and a favorable genetic background, particularly rich in genetic variants able to counteract the stress overload at the level of both nuclear and mitochondrial DNA. The integration of these factors could allow centenarians to maintain moderate levels of free radicals that exert beneficial signaling and modulator effects on cellular metabolism. Considering the hot debate on the efficacy of antioxidant supplementation in promoting healthy aging, in this review we gathered the existing information regarding genetic variability and lifestyle factors which potentially modulate the stress response at old age. Evidence reported here suggests that the integration of lifestyle factors (moderate physical activity and healthy nutrition) and genetic background could shift the balance in favor of the antioxidant cellular machinery by activating appropriate defense mechanisms in response to exceeding external and internal stress levels, and thus possibly achieving the prospect of living a longer life.

Sex- and APOE-specific genetic risk factors for late-onset Alzheimer's disease: Evidence from gene-gene interaction of longevity-related loci.

Advanced age is the largest risk factor for late-onset Alzheimer's disease (LOAD), a disease in which susceptibility correlates to almost all hallmarks of aging. Shared genetic signatures between LOAD and longevity were frequently hypothesized, likely characterized by distinctive epistatic and pleiotropic interactions. Here, we applied a multidimensional reduction approach to detect gene-gene interactions affecting LOAD in a large dataset of genomic variants harbored by genes in the insulin/IGF1 signaling, DNA repair, and oxidative stress pathways, previously investigated in human longevity. The dataset was generated from a collection of publicly available Genome Wide Association Studies, comprising a total of 2,469 gene variants genotyped in 20,766 subjects of Northwestern European ancestry (11,038 LOAD cases and 9,728 controls). The stratified analysis according to APOE*4 status and sex corroborated evidence that pathways leading to longevity also contribute to LOAD. Among the significantly interacting genes, PTPN1, TXNRD1, and IGF1R were already found enriched in gene-gene interactions affecting survival to old age. Furthermore, interacting variants associated with LOAD in a sex- and APOE-specific way. Indeed, while in APOE*4 female carriers we found several inter-pathway interactions, no significant epistasis was found in APOE*4 negative females; conversely, in males, significant intra- and inter-pathways epistasis emerged according to APOE*4 status. These findings suggest that interactions of risk factors may drive different trajectories of cognitive aging. Beyond helping to disentangle the genetic architecture of LOAD, such knowledge may improve precision in predicting the risk of dementia and enable effective sex- and APOE-stratified preventive and therapeutic interventions for LOAD.

Syndecan-4 as a genetic determinant of the metabolic syndrome.

BACKGROUND: Syndecan-4 (SDC4) is a member of the heparan sulfate proteoglycan family of cell-surface receptors. We and others previously reported that variation in the SDC4 gene was associated with several components of the metabolic syndrome, including intra-abdominal fat, fasting glucose and triglyceride levels, and hypertension, in human cohorts. Additionally, we demonstrated that high fat diet (HFD)-induced obese female mice with a Sdc4 genetic deletion had higher visceral adiposity and a worse metabolic profile than control mice. Here, we aimed to first investigate whether the mouse Sdc4 null mutation impacts metabolic phenotypes in a sex- and diet-dependent manner. We then tested whether SDC4 polymorphisms are related to the metabolic syndrome (MetS) in humans. METHODS: For the mouse experiment, Sdc4-deficient (Sdc4-/-) and wild-type (WT) mice were treated with 14-weeks of low-fat diet (LFD). Body composition, energy balance, and selected metabolic phenotypes were assessed. For the human genetic study, we used logistic regression models to test 11 SDC4 SNPs for association with the MetS and its components in a cohort of 274 (113 with MetS) elderly subjects from southern Italy. RESULTS: Following the dietary intervention in mice, we observed that the effects of the Sdc4 null mutation on several phenotypes were different from those previously reported in the mice kept on an HFD. Nonetheless, LFD-fed female Sdc4-/- mice, but not males, displayed higher levels of triglycerides and lower insulin sensitivity at fasting than WT mice, as seen earlier in the HFD conditions. In the parallel human study, we found that carriers of SDC4 rs2228384 allele C and rs2072785 allele T had reduced risk of MetS. The opposite was true for carriers of the SDC4 rs1981429 allele G. Additionally, the SNPs were found related to fasting triglyceride levels and triglyceride glucose (TyG) index, a reliable indicator of insulin resistance, with sex-stratified analysis detecting the association of rs1981429 with these phenotypes only in females. CONCLUSIONS: Altogether, our results suggest that SDC4 is an evolutionary conserved genetic determinant of MetS and that its genetic variation is associated with fasting triglyceride levels in a female-specific manner.

Occupation, Literacy, Anthropometric Traits, and Life Expectancy of Italian Men Born 1900-1910: Evidence From Military Conscription Registers.

OBJECTIVE: The aim is to explore the role of anthropometric traits and sociodemographic characteristics on human survival. METHODS: Anthropometrics and sociodemographic data of 1944 conscripts born in the first decade of the 20th century in rural municipalities of Calabria (Southern Italy) who underwent medical examinations for military service were collected. Medical examinations were linked to individual survival data. RESULTS: Height and type of occupation influenced life expectancy. For taller men, the risk of mortality increases by about 20% when compared with men with middle height, while farmers exhibited a significant survival advantage compared to those with other working experiences. DISCUSSION: Height and type of occupation were associated with human mortality. These results are likely to be related to the effect of healthy dietary patterns and physical activity on life expectancy. Further studies are needed to understand to what extent these results obtained in a rural context can be generalized to other contexts.

The Shortening of Leukocyte Telomere Length Contributes to Alzheimer's Disease: Further Evidence from Late-Onset Familial and Sporadic Cases.

Telomeres are structures at the ends of eukaryotic chromosomes that help maintain genomic stability. During aging, telomere length gradually shortens, producing short telomeres, which are markers of premature cellular senescence. This may contribute to age-related diseases, including Alzheimer's disease (AD), and based on this, several studies have hypothesized that telomere shortening may characterize AD. Current research, however, has been inconclusive regarding the direction of the association between leukocyte telomere length (LTL) and disease risk. We assessed the association between LTL and AD in a retrospective case-control study of a sample of 255 unrelated patients with late-onset AD (LOAD), including 120 sporadic cases and 135 with positive family history for LOAD, and a group of 279 cognitively healthy unrelated controls, who were all from Calabria, a southern Italian region. Following regression analysis, telomeres were found significantly shorter in LOAD cases than in controls (48% and 41% decrease for sporadic and familial cases, respectively; p < 0.001 for both). Interestingly, LTL was associated with disease risk independently of the presence of conventional risk factors (e.g., age, sex, MMSE scores, and the presence of the APOE-ε4 allele). Altogether, our findings lend support to the notion that LTL shortening may be an indicator of the pathogenesis of LOAD.

Biomarkers of Frailty: miRNAs as Common Signatures of Impairment in Cognitive and Physical Domains.

The past years have seen an increasing concern about frailty, owing to the growing number of elderly people and the major impact of this syndrome on health and social care. The identification of frail people passes through the use of different tests and biomarkers, whose concerted analysis helps to stratify the populations of patients according to their risk profile. However, their efficiency in prognosis and their capability to reflect the multisystemic impairment of frailty is discussed. Recent works propose the use of miRNAs as biological hallmarks of physiological impairment in different organismal districts. Changes in miRNAs expression have been described in biological processes associated with phenotypic outcomes of frailty, opening intriguing possibilities for their use as biomarkers of fragility. Here, with the aim of finding reliable biomarkers of frailty, while considering its complex nature, we revised the current literature on the field, for uncovering miRNAs shared across physical and cognitive frailty domains. By applying in silico analyses, we retrieved the top-ranked shared miRNAs and their targets, finally prioritizing the most significant ones. From this analysis, ten miRNAs emerged which converge into two main biological processes: inflammation and energy homeostasis. Such markers, if validated, may offer promising capabilities for early diagnosis of frailty in the elderly population.

The Genetic Variability of Members of the SLC38 Family of Amino Acid Transporters (SLC38A3, SLC38A7 and SLC38A9) Affects Susceptibility to Type 2 Diabetes and Vascular Complications.

Type 2 Diabetes (T2D) is a metabolic disease associated with long-term complications, with a multifactorial pathogenesis related to the interplay between genetic and modifiable risk factors, of which nutrition is the most relevant. In particular, the importance of proteins and constitutive amino acids (AAs) in disease susceptibility is emerging. The ability to sense and respond to changes in AA supplies is mediated by complex networks, of which AA transporters (AATs) are crucial components acting also as sensors of AA availability. This study explored the associations between polymorphisms in selected AATs genes and T2D and vascular complications in 433 patients and 506 healthy controls. Analyses revealed significant association of SLC38A3-rs1858828 with disease risk. Stratification of patients based on presence/absence of vascular complications highlighted significant associations of SLC7A8-rs3783436 and SLC38A7-rs9806843 with diabetic retinopathy. Additionally, the SLC38A9-rs4865615 resulted associated with chronic kidney disease. Notably, these genes function as AAs sensors, specifically glutamine, leucine, and arginine, linked to the main nutrient signaling pathway mammalian target of rapamycin complex 1 (mTORC1). Thus, their genetic variability may contribute to T2D by influencing the ability to properly transduce a signal activating mTORC1 in response to AA availability. In this scenario, the contribution of dietary AAs supply to disease risk may be relevant.

A common polymorphism in the UCP3 promoter influences hand grip strength in elderly people.

The reduction of muscle mass in the elderly is widely studied as one of the most important landmark of human aging. This process, which occurs for the decay of the correct energetic and protein metabolism, has important functional consequences on individual functionality but also on metabolic adaptation and immunological response to environmental challenges. Uncoupling Protein 3 (UCP3) gene is expressed in skeletal muscle where it regulates fatty acid metabolism, redox state, and ROS formation. Considering the importance of these processes in aging, we studied two variants of the UCP3 gene in a large, aged (age range 65-105) population of southern Italy verifying if these variants were correlated to hand grip strength, the most reliable measure of muscle decay. We found that a previously described functional polymorphism, rs1800849, located in the promoter region of the UCP3 gene, has a significant impact on hand grip strength. In fact, the carriers of rs1800849 T allele showed higher hand grip than the remaining of the population. Since this allele has been reported to promote a higher expression of the gene, we conclude that a more efficient uncoupling process has a beneficial effect on the aging muscle by slowing down its age related decay.

Telomere length as a function of age at population level parallels human survival curves.

Telomeres are subject to age related shortening which can be accelerated by oxidative stress and inflammation. Many studies have reported an inverse correlation between telomere length and survival, but such inverse correlation has not been always confirmed in different populations. We analyzed the trend of Leukocyte Telomere Length (LTL) as a function of age in a cohort of 516 subjects aged 65-106 years from Southern Italy. The trend of LTL obtained was quite similar to demographic survival curves reported with data of western societies. We observed a decrease of LTL after 70 years of age and then an increase after 92 years, in agreement with the sharp decrease of survival after 70 years of age and its increase after 90 years, due to the deceleration of mortality at old ages. Our data suggest that a generalized LTL attrition after 70 years of age, associated to organismal decline, affects most of the population. Such generalized attrition may exacerbate senescence in these subjects, predisposing them to high mortality risk. Conversely, the subjects with better physical conditions, experience a lower attrition and, consequently, a delayed senescence, contributing to the deceleration of mortality which has been observed among very old subjects in modern societies.

Omics in a Digital World: The Role of Bioinformatics in Providing New Insights Into Human Aging.

BACKGROUND: Aging is a complex phenotype influenced by a combination of genetic and environmental factors. Although many studies addressed its cellular and physiological age-related changes, the molecular causes of aging remain undetermined. Considering the biological complexity and heterogeneity of the aging process, it is now clear that full understanding of mechanisms underlying aging can only be achieved through the integration of different data types and sources, and with new computational methods capable to achieve such integration. RECENT ADVANCES: In this review, we show that an omics vision of the age-dependent changes occurring as the individual ages can provide researchers with new opportunities to understand the mechanisms of aging. Combining results from single-cell analysis with systems biology tools would allow building interaction networks and investigate how these networks are perturbed during aging and disease. The development of high-throughput technologies such as next-generation sequencing, proteomics, metabolomics, able to investigate different biological markers and to monitor them simultaneously during the aging process with high accuracy and specificity, represents a unique opportunity offered to biogerontologists today. CRITICAL ISSUES: Although the capacity to produce big data drastically increased over the years, integration, interpretation and sharing of high-throughput data remain major challenges. In this paper we present a survey of the emerging omics approaches in aging research and provide a large collection of datasets and databases as a useful resource for the scientific community to identify causes of aging. We discuss their peculiarities, emphasizing the need for the development of methods focused on the integration of different data types. FUTURE DIRECTIONS: We critically review the contribution of bioinformatics into the omics of aging research, and we propose a few recommendations to boost collaborations and produce new insights. We believe that significant advancements can be achieved by following major developments in bioinformatics, investing in diversity, data sharing and community-driven portable bioinformatics methods. We also argue in favor of more engagement and participation, and we highlight the benefits of new collaborations along these lines. This review aims at being a useful resource for many researchers in the field, and a call for new partnerships in aging research.

IP6K3 and IPMK variations in LOAD and longevity: Evidence for a multifaceted signaling network at the crossroad between neurodegeneration and survival.

Several studies reported that genetic variants predisposing to neurodegeneration were at higher frequencies in centenarians than in younger controls, suggesting they might favor also longevity. IP6K3 and IPMK regulate many crucial biological functions by mediating synthesis of inositol poly- and pyrophosphates and by acting non-enzymatically via protein-protein interactions. Our previous studies suggested they affect Late Onset Alzheimer Disease (LOAD) and longevity, respectively. Here, in the same sample groups, we investigated whether variants of IP6K3 also affect longevity, and variants of IPMK also influence LOAD susceptibility. We found that: i) a SNP of IP6K3 previously associated with increased risk of LOAD increased the chance to become long-lived, ii) SNPs of IPMK, previously associated with decreased longevity, were protective factors for LOAD, as previously observed for UCP4. SNP-SNP interaction analysis, including our previous data, highlighted phenotype-specific interactions between sets of alleles. Moreover, linkage disequilibrium and eQTL data associated to analyzed variants suggested mitochondria as crossroad of interconnected pathways crucial for susceptibility to neurodegeneration and/or longevity. Overall, data support the view that in these traits interactions may be more important than single polymorphisms. This phenomenon may contribute to the non-additive heritability of neurodegeneration and longevity and be part of the missing heritability of these traits.