Several germ line genes become ectopically expressed in somatic tissues of long-lived C. elegans mutants. Somatically-expresssed germ line factors appear to serve a crucial function, as knocking down any of these genes drastically reduces longevity only in the long-lived mutants (Ewen-Campen et al., 2010).
RNAi against the germ line-restricted genes abrogated longevity conferred by daf-2 mutation, while in wild-type it resulted in increased longevity. A rational explanation is that in wild-type, germ-line restricted genes are only present in the germ line. Their knockdown has no effect on somatic tissue, but might reduce the activity of the germ line cells. Ablating the gonad has life-span extending consequences in wild-type.
Such factors may operate as an interacting module, capable of being induced by a variety of upstream signals. Downstream targets of germ line factors have evolved in lineage-specific ways (Ewen-Campen et al., 2010).
In CeMM is dramatically increased in expression, which is upregulated in lin-35; slr-2 double mutant. Knockdown or overexpression of DR-essential aak-2/AMPK (Curtis et al., 2006) decrease or increase lifespan by around 14% respectively.
Ectopic expression of DAF-16/foxo in somatic tissue induces the ectopic expression of germ-line genes. Foxo overexpression transfers stem cell character to terminally differentiated cells [23].
A very active variant of FoxO3 is enriched in centanarians [9-13].
FoxO3a participates in the maintenance of adult hematopitic stem cells [14,15] as well as neural stem cells [16,17], while FoxO1 is important for embryonic stem cell maintenance [18].
Flachsbart F, et al. (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci USA 106(8):2700–2705.
Jünger MA, et al. (2003) The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J Biol 2(3):20.
Kenyon C (2010) A pathway that links reproductive status to lifespan in Caeno- rhabditis elegans. Ann N Y Acad Sci 1204:156–162.
Li Y, et al. (2009) Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 18(24):4897–4904.
Salih DA, Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20(2):126–136.
Miyamoto K, et al. (2007) Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1(1):101–112.
Tothova Z, Gilliland DG (2007) FoxO transcription factors and stem cell homeostasis: Insights from the hematopoietic system. Cell Stem Cell 1(2):140–152.
Zhang X, et al. (2011) FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nat Cell Biol 13(9):1092–1099.
Curran SP, Wu X, Riedel CG, Ruvkun G (2009) A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants. Nature 459(7250):1079–1084.
