Table 1.
The impact of aging on lifespans.
| The molecular hallmarks of age | Age-related changes | Reference |
|---|---|---|
| Genomic instability | ||
| Nuclear DNA | Chromosomal aneuploidies and copy number variations | [71–73] |
| Mitochondrial DNA | Replication errors cause polyclonal expansion of mtDNA mutations | [74] |
| Telomere exhaustion | Shortened telomeres exhibit decreased lifespans | [75, 76] |
| Epigenetic alterations | ||
| Histone modifications | Deficiency in SIRT6 exhibits accelerated aging | [77] |
| DNA methylation | Polycomb target genes become hypermethylated with age | [78] |
| Chromatin remodeling | HP1α effects longevity in flies | [79] |
| Transcriptional alterations | Micro-RNA mir-71 is required for the lifespan extension | [80] |
| Loss of proteostasis | ||
| Chaperone-mediated protein folding and stability | HSPs decline on longevity Accumulation and aggregation of abnormal proteins occur in aged organism |
[81, 82] |
| Delay or dysfunction of autophagy | mTOR signaling in the regulation of mammalian lifespan | [83] |
| The ubiquitin-proteasome system | Enhancement of proteasome activity extends replicative lifespan in yeast | [84] |
| Deregulated nutrient sensing | ||
| The insulin- and IGF-1-signaling pathway | Levels decline and dysfunction of GH/IGF-1 signaling pathway | [39, 85] |
| mTOR and AMPK | Inhibition of mTOR/DR pathway extends lifespan | [86, 87] |
| Mitochondrial dysfunction | ||
| ROS | Amphibious effects of ROS on aging | [88–91] |
| Mitochondrial Integrity and Biogenesis | Reduced efficiency of telomerase activation with aging | [92] |
| Cellular senescence | ||
| The INK4a/ARF Locus | Ink4a/ARF expression increases aging | [93, 94] |
| Stem cell attrition | Hematopoiesis declines with age resulting in a diminished production of adaptive immune cells Reduced in cell-cycle activity of hematopoietic stem cells (HSCs) on aged mice |
[7, 95] |
| Inflammation | Activation of the NLRP3 inflammasome leading to increased production of IL-1β, TNF, and interferons | [36, 96] |
SIRT6: sirtuin-6; HP1α: heterochromatin protein 1α; HSPs: heat shock proteins; mTOR: mammalian target of rapamycin; IGF-1: insulin/insulin growth factor 1; DR: dietary restriction; ROS: reactive oxygen species; AMPK: AMP-activated protein kinase; HSCs: hematopoietic stem cells; NLRP3: nucleotide-binding domain, leucine rich family (NLR), pyrin containing 3; IL-1β: interleukin-1β; TNF: tumor necrosis factor.