- Week 23: Hallmarks of ageing - Unicellular organisms will also undergo ageing and birth - Old/elderly: pensioner age around 6 - Aging: frailty, increase in vulnerability, loss of viability - Gerontology: study of waging - Geriatrics: medical aspects of aging - Segmental progerioid syndromes - Mutations in NER genes are associated with: Xeroderma pigmentosum, Cockayne syndrome, Trychothiodystrophy - Hutchinson-Gilford progeria (HGPS) - Werner syndrome - Atherosclerosis - Osteoporosis: typically in the hip - Hyperkeratosis, dry skin - Free radical theory - Mitochondrial theory of ageing - "Replicative scenescense": due to erosion of telomeres - Epidermis - Dermis - Hypodermis: loss of subcutaneous fat, loss of padding and insulation - Hallmarks of ageing - Cancer is a consequence of aberrant gain of cellular f i tness - Ageing is loss of cellular f i tness - https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12841 - https://www.cell.com/fulltext/S0092-8674(13)00645-4 - Genomic instability - Comet assay: DNA damage accumulates in haematopoietic stem cells during ageing, - Comet assay is single-cell gel electrophoresis: Intact genomic DNA is in the head of the comet, Damaged DNA moves into the tail - Micronuclei as biomarkers of ageing cells - Micronuclei can be biomarkers of ageing cells - Telomere attribution - End-replication problem - okazaki fragments on lagging strand, gaps in the lagging strand - When telomeres become short, low TRF2 and POT1, causes senescence and NIEJ - Telomere length can be measured using qPCR - Epigenetic alterations - Histone proteins and DNA itself - Modif i cations: ie methylation, phosphorylation, Ubiquitination and acetylation - Detection and quantif i cation of methylated cytosines in DNA: can be done by restriction endonucleases, Bisulf i te treatment/PCR application and sonication - Senescence and aging are characterized by (A) loss of histones, (B) imbalance of activating and repressive modif i cations, (C) transcriptional changes, (D) losses and gains in heterochromatin, (E) breakdown of nuclear lamina, (F) global
hypomethylation and focal hypermethylation, and (G) chromatin remodeling. These changes are heavily dictated by (H) environmental stimuli and (I) nutrient availability that in turn (J) alter intracellular metabolite concentrations. - Loss of proteostasis - j - Deregulated nutrient sensing - mTOR is part of a lysosomal nutrient sensor complex - Mitochondrial dysfunction - Cellular senescence Healthy Healthy Stressed Unstressed Aged or Diseased Synthesis Chaperones (Hsp40/70/90) 1 Folding - Degradation Stress Response XStress Response UPS/Autophagy components (Ub/E3 Ligases/Proteasome) Folding Requirements Capacity Folding Folding Folding Requirements Capacity Folding Requirements Folding Capacity
a Damaging agent X-rays Oxygen radicals Alkylating agents Spontaneous reactions UV light Polycyclic aromatic hydrocarbons X-rays Anti-tumour agents (cis-Pt, MMC) IG G U Uracil Abasic site 8-Oxoguanine Single-strand break Base-excision repair (BER) (6-4)PP Bulky adduct CPD Interstrand cross-link Double-strand break Nucleotide-excision repair (NER) Recombinational repair (HR, E) ) Repair process Replication errors A-G Mismatch T-C Mismatch Insertion Deletion Mismatch repair b Consequences M G2 G1 S T Inhibition of: . Transcription · Replication · Chromosome segregation Mutations Chromosome aberrations (Transient) cell-cycle arrest Apoptosis (cell death) Cancer Ageing Inborn disease