The expected lifespan of Pakistani population according to a survey carried out by World Bank is expectancy in Pakistan is 65.7 years for males and 67.4 years for females, with an average of 66.5 years.1 Longevity is a multifactorial trait and various genes are thought to play an important role among which FOXO gene is of particular significance.2 FOXO proteins are a member of the Fork head Family of transcription factors which are common integration point for many important cellular processes.3 Four mammalian FOXOs - FOXO1, FOXO3, FOXO4 and FOXO6
have been documented in mammals.3 FOXO3, a key regulator in insulin/IGF-1 signaling pathway (IIS), is known to have a protective role against biological and environmental stress factors thereby resulting in longer lifespan.4
Forkhead box protein 3 (FoxO3) may positively protect against diseases by preventing both the proliferation and activation of the smooth muscle cells , whereas Forkhead box protein 6 (FoxO6
) shares some functions with FoxO1 such as stimulating gluconeogenesis that is normally suppressed by insulin signalling .
elegans) to mammals; only one FOXO gene exists in the invertebrates while mammals have 4 FOXO genes, FOXO1, FOXO3, FOXO4, and FOXO6
[29, 33, 34].
The FoxO subfamily composes of 4 members (FoxO1, FoxO3a, FoxO4, and FoxO6
) and is characterized by the forkhead DNA-binding domain and broad physiological functions [13, 14].
All these pathways have one molecular target in common, named forkhead box O (FoxO) transcription factors, a family of transcription factors that comprises four members: FoxO1/FKHR, FoxO3/FKHRL1, FoxO4/AFX, and FoxO6
. FoxOs play an important role in bone biology by enabling the maintenance of a physiologically appropriate lifespan of mature osteoblasts through their defense activities or via modulating the activity of other transcription factors such as [beta]-catenin .
FOXO is a subfamily of Forkhead Box (FOX) transcription factors, and is further divided into FOXO1, FOXO3, FOXO4 and FOXO6
(Maiese et al., 2008).
It is active in most cells and is very similar to human FOXO1, FOXO3, FOXO4 and FOXO6
Members of the forkhead box O (Foxo) family of transcription factors, including Foxo1 (previously described as FKHR), Foxo3a (FKHRL1), Foxo4 (AFX), and Foxo6
, are phosphorylated by insulin/IGF-1 through a PI3K/Akt-dependent pathway and excluded from nucleus to inhibit their transcriptional activity (Accili et al., 2004).
, a novel member of the FoxO class of transcription factors with distinct shauttling dynamics.
There are four FoxOs (FoxO1, FoxO3, FoxO4, and FoxO6
) in humans which all bind to the same consensus sequence.
Invertebrates possess only one FOXO gene, whereas mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6
The FOXO family comprises evolutionarily conserved isoforms (FOXO1, FOXO3, FOXO4, and FOXO6
in mammals, DAF-16 in C.