Dietary restriction, aging, immune functions, genomic aspects

1
Dietary restriction, aging, immune functions,
genomic aspects

• Ageing
• Increased susceptibility to infections
• disorders of autoimmunity
• immune complex diseases,
• amyloidosis, cancers,
• etc.
• In all of these Genetic changes,
• Secondary immune (Neuro-humoral-immune)
  dysfunction!

2
Immunologic theory of ageing

• Walford, 1962, 1969)
• Ageing is due to decline in immune response
• MHC - an important regulator of immune system
• influences maximum life span (LS)
• age-specific incidence of neoplasia
• rate of immunologic ageing
• affects
• DNA repair, free radical damage, reproductive
  senescence,
• mixed function oxidases, programmed senescence
  etc.

3
Dietary restriction(DR) , immune functions and
MHC

• DR exerts profound influence upon
  immunosenescence
• DR extends life span (LS) - primarily or in part
• via immune system effects and/or
• by modulating MHC gene expression

4
Dietary restriction-early observations

• DR -half of ad lib in mice
• reduce total leukocyte and esp. lymphocyte counts
  
• 48 and 72 resp., Boutwell, 1948
• DR animals
• good health,
• extreme long LS,
• robust immune responses upon stimulation

5
Dietary Restriction

• Inhibits early thymic involution,
• Retards/reverses immunosenescence of cellular
  immunity
• Ameliorates
• IL-2 production, sensitivity ,
• turnover protein syntesis of lymphocytes
• espec. CD4 (Helper T) cells.
• Increases cell mediate killing of tumor cells
• by decreasing interfering blocking atibodies?

6
Dietary Restriction

• Retards nuclotide changes in cells
• Inhibits development of ROS (Reactive Oxigen
  Substances
• Inhibits late-life increases of autoimmune
  phenomena

7
DR- benefitial effects on LS...if

• Undernutrition without malnutrition
  (R.A. Good) ?
• Long live, LS-prolonging DR derive mainly from
  energy restriction without overt nutritient
  deficiency

8
Cross-Talk between Aging and CancerThe
Epigenetic Language

• The risk of cancer increases with age
• (Progenitor) cells accumulate enough molecular
  lesions to evade the homeostatic control.
• Molecular lesions can be
• genetic (mutations, deletions, or translocations)
  and/or
• Epigenetic DNA methylation, histone
  modification which becomes altered during Aging
  and by cancer.
• Several epigenetic alterations, such as
• global hypomethylation and CpG island
  hypermethylation,
• are progressively accumulated during Aging
• and directly contribute to cell transformation.
• Others, such as
• those involved in the control of telomere length
• and several epigenetic enzymes belonging to the
  family of NAD dependent deacetylases known as
  sirtuins,
• exhibit a well-defined progression during Aging
• that is dramatically reverted in transformed
  cells.
• The biological significance of both groups of
  epigenetic modifications
• contribution to ontogenic development,
  senescence, and cell proliferation.
• FRaga M, Esteller M Ann. N.Y. Acad. Sci. 1100
  6074 (2007).