Lecture 17

Primary hallmarks are the causes of cellular damage associated with ageing: specific alterations to DNA and protein in the cell

  • Genetic instability
  • Loss of telomeres
  • Epigenetic alterations
  • Loss of proteostasis
    There are links between them
    Genomic instability
    2 major sources of DNA damage, exogenous sources and endogenous sources
  • Exogenous sources – chemical and biological agents
  • Endogenous sources – DNA replication errors, spontaneous hydrolytic reactions, reactive oxygen species (ROS)
    There are repair mechanisms, which are regarded as anti ageing – repair to DNA
  • Repaid to accelerated loss of telomeres
  • The intengrity of mitochondrial DNA (mtDNA)
    UV light can cause adduct formations, which are difficuilt to repair.
    Double strand breaks can occur as well as base damages
    Mismatch can cause by normal DNA replication
    If telomere shortenes in chromosome, its associated with ageing.
    If you can repair and extend telomere, it can be anti ageing
    Telomerase is anti-ageing
    Telomeres are repetitive seuqences at the end of the crhomsoom es
    Telomeres are typically made somewhere between 10 to 15 kilo bases in length but then they get triommed after every cell division

Once we get to a certain short length of teleomeres, cell cannot divide and that’s when ageing occurs.
Some of epigentic traits are heritable
Three main causes of epigentic trais are

  • DNA and histone methylation pattenrs
  • Acyltaltion of histones
  • Chromatin remodelling
    Methylation and acytalation
  • DNA coil around histone with tail exposed
  • Gene effectively inaccessible to transcription factors
  • This is stimulated by methylation of DNA
  • Parts of DNA that have high levels of methylation are highly compacted
    If you mehtlyated histones you get similar effect
    If histones are acytlated, it losens structure and you have access to transcitption factors
    If the DNA is methylated, the pattern of methylation can be inherited by daughter cells
    The epigenetic marks of the mother are passed down to the ova.
    At least the environmental history of the mother is passed down to the next generation
    Most sperm is wrapped around protamines. When sperm cell enters egg cell, spoerm DNA is deprotinated and protamines are replaced by female histones.
    Epigentic marks are overwritten at inception but some remain as some DNA of sperm are associasted with hisotnes
  • That has consequence for next generatio
  • Thos conserquences last more than one generation and can last 4 generations
    Epigenetic alteration associated with ageing
    Changes in histone modification (acetylation and methylation) that are strongly associated with ageing phenotype
    Chromatin remodelling is also associated with ageing phenotype

If you have normally folded protein, heat shock can unfold it, ER stress and oxidative stress can also unfold it.
Unfolded protein can aggregate, which can stimulate ageing phenotype.

Deregulating nutrient sensing
Growth hormones produced in pituatry gland
Cells responsive to groewht hormone produce insulin like growth factor
Inslunn like groewht factor signals through same pathway as insulin and is highly conserved
Deregulation of nutritnet sensing is associated with ageing
IGF- 1 levels decline with age, so less efficient insulin repsones – less signaling
IGF-1 levels falling is a response to ageing
IIS downregulation is defensive response to ageing by minimising cell growth and metabolism to prevent damaged cells
Cellular senescene – the process by which the capacity for cell division, growth, and function is lost over time.
As you get older, you accumuluate damage over long life span and also lose ability to repair and clear damage cell, so accumulate senecene cells. Affects of accumulation reduces tissue functions.
Stem cell exhaustion – if you lose hematopoetic stem cellsd you can stimulate anemia
If you lose mesenchymal stem cells you develop osteoarthritis
Some stem cellscan be deferentiated into stem cell state, which are called induced pluripotent stem cells and they rejuvenate stem cell population so they are anti ageing

White adipose tissue is source of energy

  • Has struursal functions – keeps face fat
  • Lot of visceral white adipose tissue that can be energy store
    Also has immune responses
    Obesity accelerates ageing.
    Lymphocytes from obese children have damaged DNA.
    Obese people have shorter telomeres.
    Most obese people live in western countries.
    Olive oil and increase intake of broccoli can be good for increasing lifespan.
    Nrf2 has a tsail composed of latch and hinge latch is held by Keap1.
    Keap1 targets NRF2 to proteosome.
    Oxidative stress stimulates Keap1 to let go of NRF2 which then enters the nucleus and stimulates expression of catalase and superoxide dismutase.
    Sulforapahine binds keap2 in borcolliu and inhibits preoteosome targeting. Result in increased anti oxidant activity.