Genetic and epigenetic regulation of human aging and longevity

Abstract

Here we summarize the latest data on genetic and epigenetic contributions to human aging and longevity. Whereas environmental and lifestyle factors are important at younger ages, the contribution of genetics appears more important in reaching extreme old age. Genome-wide studies have implicated ~57 gene loci in lifespan. Epigenomic changes during aging profoundly affect cellular function and stress resistance. Dysregulation of transcriptional and chromatin networks is likely a crucial component of aging. Large-scale bioinformatic analyses have revealed involvement of numerous interaction networks. As the young well-differentiated cell replicates into eventual senescence there is drift in the highly regulated chromatin marks towards an entropic middle-ground between repressed and active, such that genes that were previously inactive "leak". There is a breakdown in chromatin connectivity such that topologically associated domains and their insulators weaken, and well-defined blocks of constitutive heterochromatin give way to generalized, senescence-associated heterochromatin, foci. Together, these phenomena contribute to aging.

Keywords: APOE; Aging; Epigenetics; FOXO3; Genome-wide association studies; Histones; Longevity; Network analysis; Transcription.

Fig. 1.

Aging-related protein interaction subnetwork for three well-known aging-related pathways: insulin signaling, AMPK and mTOR signaling. (From Zhang et al. [220])

Fig. 2.

The aging subnetwork consists of 192 aging genes and 561 direct interactions among these. The sizes of the nodes are proportional to their degrees of interaction in the entire protein-protein interaction network. Aging genes involved in aging-related pathways and interactions among them are both highlighted. (From Zhang et al. [220])

Fig. 3.

The gene FOXO3 interacts with its neighbors in a 46-gene cell resilience “gene factory” on chromosome 6q21 [80]. Upper panel fluorescent in situ hybridization experiments showing, on the left, position of fluores-cently-labeled FOXO3 (pale blue), HACE1 (green) and LAMA4 (red) in quiescent lymphoblastoid cell lines; and on the right, change in position of the genes in cells after activation by stress, induced by serum deprivation and H₂O₂ treatment. Lower panel schematics showing the effect; for simplicity only 5 of the 46 neighborhood genes are shown. The sphere denotes a presumed transcription center. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4.

Example of sub-network analysis result for one of the 6 genes that were prominent in the analysis. Shown are genes regulated by interferon-γ gene, IFNG, in mononuclear cells from (a) centenarians and (b) septuagenarians as compared with young individuals.(From Borras et al. [223])

Fig. 5.

Histone modification pathways. (From Li et al. [238])

Fig. 6.

The changes in chromatin states with aging. Increased cellular senescence results in a loss of heterochromatin caused by the factors depicted in the diagram. (From Booth and Brunet [256])

Fig. 7.

Epigenomic changes result in dysregulation of gene expression in aging. (From Booth and Brunet [256])

Fig. 8.

Caloric restriction regulates epigenetic processes by DNA methylation and histone modification. Via the pathways shown, this helps increase lifespan. (From: Li et al. [238])

Fig. 9.

Breakdown of the nuclear lamina, heterochromatin, and chromatin connections in senescence. With senescence comes a dissolution of the tight control of gene regulation as the inactive chromatin becomes dissociated from the nuclear envelope, topological-associated domains (TADs) lose neighboring connections in exchange for long-range interaction, and the distinction between active and inactive chromatin domains becomes blurred.