Programmatic features of aging originating in development: aging mechanisms beyond molecular damage?

The idea that aging follows a predetermined sequence of events, a program, has been discredited by most contemporary authors. Instead, aging is largely thought to occur due to the accumulation of various forms of molecular damage. Recent work employing functional genomics now suggests that, indeed, certain facets of mammalian aging may follow predetermined patterns encoded in the genome as part of developmental processes. It appears that genetic programs coordinating some aspects of growth and development persist into adulthood and may become detrimental. This link between development and aging may occur due to regulated processes, including through the action of microRNAs and epigenetic mechanisms. Taken together with other results, in particular from worms, these findings provide evidence that some aging changes are not primarily a result of a build-up of stochastic damage but are rather a product of regulated processes. These processes are interpreted as forms of antagonistic pleiotropy, the product of a “shortsighted watchmaker,” and thus do not assume aging evolved for a purpose. Overall, it appears that the genome does, indeed, contain specific instructions that drive aging in animals, a radical shift in our perception of the aging process.—de Magalhães, J. P. Programmatic features of aging originating in development: aging mechanisms beyond molecular damage?

[1]  J. Hoeijmakers,et al.  Comprehensive microRNA profiling in B-cells of human centenarians by massively parallel sequencing , 2012, BMC Genomics.

[2]  Owen T McCann,et al.  Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. , 2010, Genome research.

[3]  C. Suschek,et al.  Specific Age-Associated DNA Methylation Changes in Human Dermal Fibroblasts , 2011, PloS one.

[4]  S. Austad Is aging programed? , 2004, Aging cell.

[5]  Qingying Meng,et al.  Genetic coregulation of age of female sexual maturation and lifespan through circulating IGF1 among inbred mouse strains , 2012, Proceedings of the National Academy of Sciences.

[6]  J. P. D. Magalhães,et al.  Cognitive aging as an extension of brain development: A model linking learning, brain plasticity, and neurodegeneration , 2005, Mechanisms of Ageing and Development.

[7]  George C. Williams,et al.  PLEIOTROPY, NATURAL SELECTION, AND THE EVOLUTION OF SENESCENCE , 1957, Science of Aging Knowledge Environment.

[8]  João Pedro de Magalhães,et al.  Meta-analysis of age-related gene expression profiles identifies common signatures of aging , 2009, Bioinform..

[9]  J. Baron,et al.  Changes in gene expression associated with aging commonly originate during juvenile growth , 2010, Mechanisms of Ageing and Development.

[10]  R. Holliday Aging is No Longer an Unsolved Problem in Biology , 2006, Annals of the New York Academy of Sciences.

[11]  Lucinda K. Southworth,et al.  An elt-3/elt-5/elt-6 GATA Transcription Circuit Guides Aging in C. elegans , 2008, Cell.

[12]  M. Klass,et al.  Non-ageing developmental variant of Caenorhabditis elegans , 1976, Nature.

[13]  S. E. Miller,et al.  Developmental Arrest During Larval Life and Life-Span Extension in a Marine Mollusc , 1990, Science.

[14]  M. Blagosklonny Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition , 2006, Cell cycle.

[15]  B. A. Eales,et al.  Sex and death in the mouse: genetically delayed reproduction and senescence. , 1997, Genome.

[16]  A. Comfort Ageing : the biology of senescence , 1964 .

[17]  R. Miller,et al.  Kleemeier award lecture: are there genes for aging? , 1999, The journals of gerontology. Series A, Biological sciences and medical sciences.

[18]  R. Ricklefs,et al.  Life-history connections to rates of aging in terrestrial vertebrates , 2010, Proceedings of the National Academy of Sciences.

[19]  S. Rattan,et al.  Theories of biological aging: Genes, proteins, and free radicals , 2006, Free radical research.

[20]  Hein Putter,et al.  Persistent epigenetic differences associated with prenatal exposure to famine in humans , 2008, Proceedings of the National Academy of Sciences.

[21]  C. Finch,et al.  Next-generation sequencing in aging research: Emerging applications, problems, pitfalls and possible solutions , 2010, Ageing Research Reviews.

[22]  L. Partridge The new biology of ageing , 2010, Philosophical Transactions of the Royal Society B: Biological Sciences.

[23]  C. Mccay IS LONGEVITY COMPATIBLE WITH OPTIMUM GROWTH? , 1933, Science.

[24]  G. Church,et al.  Genomes optimize reproduction: aging as a consequence of the developmental program. , 2005, Physiology.

[25]  E. Richfield,et al.  Age-related gene-specific changes of A-to-I mRNA editing in the human brain , 2010, Mechanisms of Ageing and Development.

[26]  G. Ruvkun,et al.  Lifespan Regulation by Evolutionarily Conserved Genes Essential for Viability , 2007, PLoS genetics.

[27]  P. Kruk,et al.  A case study of “disorganized development” and its possible relevance to genetic determinants of aging , 2009, Mechanisms of Ageing and Development.

[28]  T. Kirkwood,et al.  On the Programmed/Non-Programmed Nature of Ageing within the Life History , 2011, Current Biology.

[29]  João Pedro de Magalhães,et al.  An analysis of the relationship between metabolism, developmental schedules, and longevity using phylogenetic independent contrasts. , 2007, The journals of gerontology. Series A, Biological sciences and medical sciences.

[30]  B. Korn,et al.  DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells , 2010, Aging cell.

[31]  T. Kirkwood Understanding ageing from an evolutionary perspective , 2008, Journal of internal medicine.

[32]  F. Slack,et al.  A Developmental Timing MicroRNA and Its Target Regulate Life Span in C. elegans , 2005, Science.

[33]  C. Kenyon The genetics of ageing , 2010, Nature.

[34]  J. P. D. Magalhães Is mammalian aging genetically controlled? , 2004, Biogerontology.

[35]  L. Hayflick How and why we age , 1994, Experimental Gerontology.

[36]  D. Bredesen The non‐existent aging program: how does it work? , 2004, Aging cell.

[37]  J. de Magalhães,et al.  GenAge: a genomic and proteomic network map of human ageing , 2004, FEBS letters.

[38]  C. Rollo Growth negatively impacts the life span of mammals , 2002, Evolution & development.

[39]  M. Lachmann,et al.  MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain. , 2010, Genome research.

[40]  Cornelia I Bargmann,et al.  Comparing genomic expression patterns across species identifies shared transcriptional profile in aging , 2004, Nature Genetics.

[41]  João Pedro de Magalhães,et al.  A review and appraisal of the DNA damage theory of ageing. , 2011, Mutation research.

[42]  J. Thaden,et al.  Remarkable longevity and stress resistance of nematode PI3K‐null mutants , 2008, Aging cell.

[43]  Leonard Hayflick,et al.  Entropy Explains Aging, Genetic Determinism Explains Longevity, and Undefined Terminology Explains Misunderstanding Both , 2007, PLoS genetics.

[44]  K. Kitagawa,et al.  Developmental and age-related changes in apolipoprotein B mRNA editing in mice. , 1992, Journal of lipid research.

[45]  N. Wolf Comparative biology of aging , 2009 .

[46]  C. Finch,et al.  The Regulation of Physiological Changes During Mammalian Aging , 1976, The Quarterly Review of Biology.

[47]  Jan Vijg,et al.  Puzzles, promises and a cure for ageing , 2008, Nature.

[48]  J. Baron,et al.  Coordinated postnatal down‐regulation of multiple growth‐promoting genes: evidence for a genetic program limiting organ growth , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[49]  J. Mitteldorf,et al.  Programmed and altruistic ageing , 2005, Nature Reviews Genetics.

[50]  R. Walker Developmental theory of aging revisited: focus on causal and mechanistic links between development and senescence. , 2011, Rejuvenation research.

[51]  M. Takasugi Progressive age-dependent DNA methylation changes start before adulthood in mouse tissues , 2011, Mechanisms of Ageing and Development.

[52]  M. Raff The mystery of intracellular developmental programmes and timers. , 2006, Biochemical Society transactions.