Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases

Abstract

Ageing is the predominant risk factor for many common diseases. Human premature ageing diseases are powerful model systems to identify and characterize cellular mechanisms that underpin physiological ageing. Their study also leads to a better understanding of the causes, drivers and potential therapeutic strategies of common diseases associated with ageing, including neurological disorders, diabetes, cardiovascular diseases and cancer. Using the rare premature ageing disorder Hutchinson-Gilford progeria syndrome as a paradigm, we discuss here the shared mechanisms between premature ageing and ageing-associated diseases, including defects in genetic, epigenetic and metabolic pathways; mitochondrial and protein homeostasis; cell cycle; and stem cell-regenerative capacity.

Figure 1 |. Cellular ageing defects.

An overview of the cellular ageing defects that underlie premature ageing disorders, regular ageing and ageing-associated disease. These ageing defects are interconnected and include reduced DNA repair pathway efficiency, loss of genomic integrity, a global loss of heterochromatin, alterations in metabolic signalling, increased formation of reactive oxygen species (ROS) by mitochondria, reduced activity of proteostasis-promoting proteolytic pathways and activation of senescence pathways. Post-translational processing of wild-type prelamin A by the zinc metalloproteinase ZMPSTE24 releases mature wild-type lamin A that is incorporated in the nuclear lamina (indicated in the left half of the cell nucleus). In the premature ageing disease Hutchinson–Gilford progeria syndrome (HGPS), the LMNA^G608G mutation activates a cryptic splice site that results in the formation of a prelamin A isoform lacking 50 amino acids, including the ZMPSTE24 cleavage site, and is named progerin (indicated in the right half of the cell nucleus). Incorporation of this mutant isoform into the nuclear lamina distorts the nuclear shape and further contributes to other ageing defects shown in the figure (thin arrows indicate dysregulated pathways and mechanisms). AMPK, AMP-activated protein kinase; HR, homologous recombination; IL-1, interleukin-1; NER, nucleotide excision repair; NHEJ, non-homologous end joining; NF-κB, nuclear factor-κB; PGC1α, proliferator-activated receptor-γ co-activator 1α; SIRT1, sirtuin 1.

Figure 2 |. Defects in DNA damage repair associated with ageing.

An overview of DNA repair pathways that are impaired in premature ageing syndromes, ageing and ageing-associated diseases. Thin arrows indicate the DNA repair proteins that are impaired specifically in Hutchinson–Gilford progeria syndrome (HGPS). Double-strand breaks are either repaired by homologous recombination through RAD51-mediated repair using the sister chromosome as a template, or X-ray repair cross-complementing protein 6 (XRCC6)- and DNA protein kinase catalytic subunit (PKcs)-mediated non-homologous end joining of the broken ends. Poly(ADP-ribose) polymerase 1 (PARP1) promotes ataxia telangiectasia mutated (ATM)-dependent DNA damage signalling activation. In nucleotide excision repair, bulky DNA adducts are excised, and the resulting single-strand DNA breaks are repaired by the indicated proteins. The final step of repair for each repair pathway includes DNA ligase-mediated joining of the DNA strands at the breakage point. PCNA, proliferating cell nuclear antigen.

Figure 3 |. Epigenetic defects associated with ageing.

An overview of the epigenetic alterations (indicated by thin arrows) on the histone H3 tail that contribute to global loss of heterochromatin in Hutchinson–Gilford progeria syndrome (HGPS) and are associated with ageing and ageing-associated diseases. Decreased levels of EZH2 reduce the trimethylation (indicated by the 3 green hexagons) of histone H3 at lysine 27 (H3K27) by the Polycomb repressive complex 2 (PRC2) Polycomb group (PCG) protein complex, which is a repressive chromatin mark that enables binding of the PRC1 PcG complex and the subsequent trimethylation (H3K9me3), which can bind heterochromatin protein 1 homologue-α (HP1α); these methylation levels are decreased in HGPS. H3K9me3 has been reported to be downregulated in cells from patients with HGPS but was conversely found to be upregulated in a Zmpste24-knockout progeria-like mouse model^,. Various proteins within the nucleosome remodelling and deacetylase (NuRD) complex have decreased expression levels in HGPS, which reduces the histone deacetylation activity of this complex. H3K9 and H3K27 acetylation (indicated by red triangles) are expression-permissive chromatin marks that are thought to be mutually exclusive to the repressive trimethylation marks on the same lysines. HDAC1, histone deacetylase 1; RBB4, RB-binding protein 4.

Figure 4 |. Mitochondrial ROS-driven ageing defects.

Mitochondrial oxidative phosphorylation in ageing and ageing-associated diseases (AADs) is driven by a decrease in insulin-like growth factor 1 (IGF1) signalling, or uncoupling of IGF1 and mTOR signalling resulting from chronic activation of the IGF-1 pathway (indicated by interruption of arrow), and increased activation of mTOR, resulting from impaired AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) signalling. Increased formation of reactive oxygen species (ROS) due to increased mitochondrial activity, decreased levels of antioxidants and decreased PCG1α (peroxisome proliferator-activated receptor-γ co-activator 1α) activity, resulting in impaired mitochondrial biogenesis and turnover, causes damage to DNA, proteins and other macromolecules. Decreased efficiency of DNA repair pathways and proteostasis pathways, including autophagy and ubiquitin–proteasome system (UPS)-mediated degradation of damaged proteins, during (premature) ageing and in AADs further contributes to the deleterious effects of ROS on mitochondrial integrity and cellular homeostasis.

Figure 5 |. Cellular senescence pathways.

Chronic levels of elevated DNA damage and metabolic-induced cellular stress trigger the activation of p16 and p53 in Hutchinson–Gilford progeria syndrome (HGPS), ageing and ageing-associated diseases (indicated by arrows), through which activation of RB and p21 results in permanent senescent growth arrest. Increased activation of transforming growth factor β (TGFβ) and nuclear factor-κβ (NF-κB) drive the senescent-associated secretory phenotype (SASP), which is characterized by the indicated inflammatory regulators. COX2, cyclooxygenase 2; CXCL1, C-X-C motif chemokine 1; TNFα, tumour necrosis factor-α.