a b s t r a c t
Vitamin D deficiency has been linked to many human diseases such as Alzheimer's disease (AD), Parkinson's
disease (PD), multiple sclerosis (MS), hypertension and cardiovascular disease. A Vitamin D
phenotypic stability hypothesis, which is developed in this review, attempts to describe how this vital
hormone acts to maintain healthy cellular functions. This role of Vitamin D as a guardian of phenotypic
stability seems to depend on its ability to maintain the redox and Ca2þ signalling systems. It is argued
that its primary action is to maintain the expression of those signalling components responsible for
stabilizing the low resting state of these two signalling pathways. This phenotypic stability role is
facilitated through the ability of vitamin D to increase the expression of both Nrf2 and the anti-ageing
protein Klotho, which are also major regulators of Ca2þ and redox signalling. A decline in Vitamin D
levels will lead to a decline in the stability of this regulatory signalling network and may account for why
so many of the major diseases in man, which have been linked to vitamin D deficiency, are associated
with a dysregulation in both ROS and Ca2þ signalling.