RESUMO
Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.
Assuntos
Apolipoproteína C-I/genética , Apolipoproteínas E/genética , Loci Gênicos , Longevidade/genética , Proteínas de Membrana Transportadoras/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Mapeamento Cromossômico , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 19 , Análise por Conglomerados , Europa (Continente) , Ligação Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Escore Lod , Pessoa de Meia-Idade , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , IrmãosRESUMO
Immunosenescence is characterized by three main aspects: (i) the shrinkage of the T cell repertoire and the accumulation of oligoclonal expansions (megaclones) of memory/effector cells directed toward ubiquitary infectious agents; (ii) the involution of the thymus and the exhaustion of naïve T cells; and (iii) a chronic inflammatory status called inflamm-aging. We present here possible strategies to counteract these main aspects of immunosenescence in humans with particular attention to the reduction of antigenic load by pathogens, such as CMV, and the normalization of intestinal microflora, the possible utilization of IL-7 to reverse thymic involution, the purging of megaclones, the forced expression of CD28 on T lymphocytes, the reduction of inflamm-aging and the administration of nutrients such as vitamin D. Possible drawbacks of all these strategies are discussed. Finally, the complexity of a rejuvenation approach is stressed, with particular attention to the inhibitory role played by the "old microenvironment" on the performance of progenitor cells, the best candidate to counteract the decline in regenerative potential characteristic of organs and tissues from old organisms.
Assuntos
Envelhecimento/imunologia , Sistema Imunitário/crescimento & desenvolvimento , Inflamação/imunologia , Linfócitos T/imunologia , Timo/imunologia , Antígenos/imunologia , Evolução Biológica , Citomegalovirus/imunologia , Infecções por Citomegalovirus/imunologia , HumanosRESUMO
The main message of this review can be summarized as follows: aging and longevity, as complex traits having a significant genetic component, likely depend on a number of nuclear gene variants interacting with mtDNA variability both inherited and somatic. We reviewed the data available in the literature with particular attention to human longevity, and argued that what we hypothesize for aging and longevity could have a more general relevance and be extended to other age-related complex traits such as Alzheimer's and Parkinson's diseases. The genetics which emerges for complex traits, including aging and longevity, is thus even more complicated than previously thought, as epistatic interactions between nuclear gene polymorphisms and mtDNA variability (both somatic and inherited) as well as between mtDNA somatic mutations (tissue specific) and mtDNA inherited variants (haplogroups and sub-haplogroups) must be considered as additional players capable of explaining a part of the aging and longevity phenotype. To test this hypothesis is one of the main challenge in the genetics of aging and longevity in the next future.
Assuntos
DNA Mitocondrial/genética , Longevidade/genética , Núcleo Celular/metabolismo , Reparo do DNA/genética , Humanos , Doenças Mitocondriais/genética , Mutação/genéticaRESUMO
Aging is due to a complex interaction of genetic, epigenetic, and environmental factors, but a strong genetic component appears to have an impact on survival to extreme ages. In order to identify "longevity genes" in humans, different strategies are now available. In our laboratory, we performed association studies on a variety of "candidate" polymorphisms in Italian centenarians. Many genes/polymorphisms gave negative results, while others showed a positive association with human longevity and a sometimes-positive association with unsuccessful aging (myocardial infarction, Alzheimer's disease, and type 2 diabetes). Results regarding genes involved in inflammation (IL-1 cluster, IL-6, IL-10, TNF-alpha, TGF-beta, TLR-4, PPARgamma), insulin/IGF-1 signaling pathway and lipid metabolism (apolipoproteins, CETP, PON1), and oxidative stress (p53, p66(shc)) will be described. In addition, a strong role of the interaction between nuclear and mitochondrial genomes (mtDNA haplogroups and the C150T mutation) emerged from our findings. Thus, the genetics of human longevity appears to be quite peculiar in a context where antagonistic pleiotropy can play a major role and genes can have a different biological role at different ages.
Assuntos
Envelhecimento/genética , Longevidade/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Apolipoproteínas/genética , Arildialquilfosfatase/genética , Proteínas de Transporte/genética , Proteínas de Transferência de Ésteres de Colesterol , Glicoproteínas/genética , Humanos , Inflamação/genética , Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Interleucina-1/genética , Interleucina-10/genética , Interleucina-6/genética , Metabolismo dos Lipídeos/genética , Longevidade/fisiologia , Família Multigênica , Estresse Oxidativo , PPAR gama/genética , Polimorfismo Genético , Proteínas Adaptadoras da Sinalização Shc , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
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 that a common core of master genes and metabolic pathways are responsible for aging and longevity across animal species. Moreover, in the concern of our plan to discover new genetic factors related to longevity, we explored the possibility to by-pass the need of an a-priori choice of candidate genes, extending the search to genes and genomic regions of still unknown function. Alu sequences may be considered as good markers of highly variable and potentially unstable loci in functionally important genomic regions. We extensively screened Alu-rich genomic sites and found a new genomic region associated with longevity.
Assuntos
Imunidade/genética , Inflamação/genética , Fator de Crescimento Insulin-Like I/metabolismo , Insulina/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Arildialquilfosfatase/genética , Genótipo , Humanos , Fator de Crescimento Insulin-Like I/genética , Interleucina-1/genética , Interleucina-10/genética , Interleucina-6/genética , Longevidade , Modelos Biológicos , Família Multigênica , Estresse Oxidativo , Polimorfismo Genético , Transdução de SinaisRESUMO
Centenarians are people who escaped from major common diseases, including cancer, and reached the extreme limits of human life-span. The analysis of demographic data indicates that cancer incidence and mortality show a levelling off around the age of 85-90 years, and suggests that oldest old people and centenarians are protected from cancer onset and progression. In this paper, we review data of recent literature on the distribution in centenarians of germ-line polymorphisms, which are supposed to affect the individual susceptibility to cancer (p53, HRAS1, BRCA1, glutathione transferases, cytochrome oxidases, steroid-5 alpha-reductase enzyme type II). Moreover, we add new data on two p53 polymorphisms in a total of 1086 people of different age, including 307 centenarians. In addition, we put forth the hypothesis that the remodelling of the immune system occurring with age is capable of creating a hostile environment for the growth of cancer cells in these exceptional individuals. We conclude that future studies on centenarians regarding the germ-line variability of genes involved in the control of the immune response, including apoptosis (ApoJ), are likely to be of fundamental importance in understanding the basic mechanisms for cancer, aging and their complex relationship.
