TY  - CHAP
M1  - Book, Section
TI  - Genetics and Aging
A1  - Martin, George M.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - The  current  unprecedented  rate  of  growth  of  the  population  over  age  85  years  underscores  the  importance  of  investigating  genetic  factors  modulating  age-related  disabilities  and  diseases.  An  equally  important  and  neglected  task,  however,  is  to  discover  genetic  factors  leading  to  unusual  degrees  of  maintenance  of  structure  and  function  in  late  life  (successful  or  elite  aging).There  are  six  stages  in  the  life  cycle  of  humans:  developing,  maturing,  reproducing,  sageing  (characterized  by  extensive  use  of  physiological  and  behavioral  compensations),  senescing  (characterized  by  increasing  degrees  of  homeostatic  failures),  and  dying.  Gene  action  at  all  of  these  stages  is  relevant  to  the  biology  of  aging.Senescence  can  occur  in  the  absence  of  overt  specific  disease  entities  but  cannot  easily  be  dissociated  from  disease  states.  Senescent  changes  in  tissues  may  be  direct  precursors  of  common  late-onset  diseases  via  mechanisms  that  remain  to  be  fully  elucidated.  One  example  is  somatic  mutation,  a  precursor  of  the  many  neoplasms  that  emerge  in  late  life.  Late-onset  diseases  may  therefore  be  viewed  as  senescent  phenotypes.Senescent  phenotypes  are  nonadaptive  traits  that  occur  because  of  the  decline  in  the  force  of  natural  selection  with  respect  to  the  age  of  gene  effects.  Senescence  is  not  “programmed”  in  the  sense  that  determinative,  sequential  gene  action  programs  development.Two  broad  classes  of  gene  action  are  postulated  to  differentially  modulate  senescent  phenotypes  and  life  span.  The  first  involves  constitutional  mutations  with  neutral  effects  on  reproductive  fitness  but  with  deleterious  effects  late  in  the  life  course,  thus  escaping  the  force  of  natural  selection.  These  modulations  can  be  regarded  as  private  in  that  their  frequencies  in  various  populations  are  largely  functions  of  genetic  drift.  The  second  involves  genes  with  antagonistic  pleiotropic  actions.  These  involve  allelic  variants  selected  to  enhance  reproductive  fitness  but  with  deleterious  effects  late  in  the  life  course.  Because  such  alleles  are  likely  to  spread  widely  within  many  populations,  they  can  be  considered  to  lead  to  public  modulations  of  senescence.  Polymorphisms,  rather  than  rare  mutations,  are  more  likely  to  be  responsible  for  differential  public  modulations  within  populations.It  is  probably  the  case  that  variants  at  thousands  of  genetic  loci  have  the  potential  to  modulate  the  pathobiology  of  senescence.  These  can  be  divided  into  two  classes:  variants  that  lead  to  segmental  progeroid  syndromes,  which  impact  upon  multiple  senescent  phenotypes,  and  variants  that  lead  to  unimodal  progeroid  syndromes,  which  impact  upon  a  single  tissue  or  phenotype.  The  prototypic  example  of  a  segmental  progeroid  syndrome  is  the  Werner  syndrome  (“Progeria  of  The  Adult”).  It  is  caused  by  null  mutations  at  a  member  of  the  RecQ  class  of  DNA  helicases  and  leads  to  accelerated  replicative  senescence  and  a  mutator  phenotype.  Although  it  is  best  viewed  as  a  private  modulation  of  aging,  polymorphic  forms  of  the  gene  might  prove  to  be  of  more  general  significance.  Examples  of  unimodal  progeroid  syndromes  include  familial  forms  of  dementias  of  the  Alzheimer  type.  These  are  also  rare  private  modulations,  but  these  may  inform  us  as  to  general  pathogenetic  mechanisms.  The  apolipoprotein  E  locus,  however,  serves  as  an  example  of  a  public  polymorphic  modulation  of  that  disorder.A  highly  polygenic  basis  for  senescence  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/18
UR  - ommbid.mhmedical.com/content.aspx?aid=1181401371
ER  -