Abstract:The growth-cessation subroutine mediates the shut-down of cellular proliferation already in young/middle age and continues so with increasing age.
Several genes were found to be highly correlated with postnatal-development and are potential candidates to mediate this subroutine.
MYCN (alias n-Myc) is actually a circadian gene that is suppressed during the juvenile growth phase and also downregulated by dietary restriction in multiple tissues. n-Myc is similar to c-Myc. Both belong to the same family. n-Myc interacts with c-Myc. They are probably circadian because they bind to the E-box element. Circadian expression of c-MYC is modulated by HDAC inhibitor Trichostatin A (also known as TSA) [Repouskou et al. 2010], a drug that extends the lifespan in model organisms [15346199]. c-Myc is one of the legendary factors that mediate cellular reprogramming. n-Myc can functionally replace c-Myc [10837031] and even substitute for c-Myc as a reprogramming factor [18371358].
LIN28B has cold-shock domain (cold-shock proteins are just like heat-shock proteins but for cold shock, i.e. stress resistance). It is also highly expressed in the germline (of which the cells are especially resistance against aging). It is functional related to LIN28 which is also one of the factors that are capable of promoting reprogramming of adult somatic cells into induced pluripotent stem cells (actually just as everything which is anti-aging).
LET-7 is a heterochronic (developmental change in timing of events) RNA. let-7 family members repress cell cycle regulators (Cdks, etc.). Let-7 expression increases with age in mouse. LET-7b miRNA expression is positively correlated with age and age-related diseases such as cataracts in humans [http://bjo.bmj.com/content/96/5/747.short?rss=1]. Let-7 itself represses its own inhibitor LIN28B as well as the activator of its own inhibitor (c-Myc). c-Myc itself suppresses let-7 directly. Among the major target genes of let-7 are also oncogenes like RAS and HMGA2.
HMGA2 is highly expressed in early development but almost undetectable in adult tissues. Mice with loss-of-function in Hmga2 are probably short lived as they will have an accelerated growth cessation subroutine. Hmga2 is highly expressed in adult neural stem cells and its level declines with age [18957199].
Cyclin-dependent kinase 6 (Cdk6) is associated with juvenile growth and it is clock-modulator as well as pacemaker that leads to long period phenotype if silenced in cells.
EGF-containing fibulin-like extracellular matrix protein 1 (Efemp1) is induced in expression during aging in multiple tissues, but its knockout seems to result in premature aging. Efemp1 is the strongest coexpressed gene of Zbtb16 [http://www.genefriends.org], a circadian transcription factor that is upregulated during the juvenile growth phase, but downregulated during aging and overexpressed upon dietary restriction.
Guanine nucleotide binding protein (G protein) alpha 12 (GNA12) is associated with juvenile growth.
ZBTB32 is a zinc finger containing kasio protein that forms complexes with methyl-CpG-binding proteins and HDACs.
Repouskou, A., Sourlingas, T.G., Sekeri-Pataryas, K.E., and Prombona, A. (2010). The circadian expression of c-MYC is modulated by the histone deacetylase inhibitor trichostatin a in synchronized murine neuroblastoma cells. Chronobiol Int 27, 722-741.
