Deleterious Roles of Infl ammatory Adhesion Molecules during Aging - Adhesion Molecules - page 78

factors is a possible converging process linking normal aging and the pathogenesis
of age-related diseases (Chung et al. 2006).
AMs IN AGE-RELATED DISEASES
AMs have received much attention, not only for the essential roles they have in
normal physiological processes, but also for their deleterious roles as modulators
of uncontrolled cell-cell interactions, which contribute to the vascular dysfunction
and tissue injury associated with diseases. Because of the increased incidence of
these diseases with age, it is important to recognize the age-associated upregulation
of AMs that plays a crucial role in the initiation and development of age-related
diseases such as cardiovascular diseases, immunosenescence, cancer, and
neurodegenerative diseases, as illustrated in a few of the following examples.
Atherosclerosis
Evidence clearly shows increased arterial susceptibility to atherogenetic stimuli with
age. In a rabbit model of atherosclerosis, soon at er initiating an atherogenic diet,
microscopic examination revealed leukocyte attachment to the intima-lining ECs.
VCAM-1 is proved to be involved in this adhesion at sites of atheroma initiation.
An increased VCAM-1 level plus high plasma cholesterol was suspected as an
underlying cause of atherosclerosis during aging. Experiments with hypomorphic
variants of VCAM-1 introduced into mice that are rendered susceptible to
atherogenesis (by inactivation of the apolipoprotein E gene) show reduced lesion
formation. In addition to VCAM-1, P- and E-selectin also contribute to leukocyte
recruitment in atherosclerosis-susceptible mice.
h e mechanism of VCAM-1 induction at er the initiation of an atherogenic
diet likely involves the inl ammatory process instigated by modii ed lipoprotein
particles accumulating in the arterial intima in response to hyperlipidemia.
Constituents of modii ed lipoprotein particles, among them certain oxidized
phospholipids and short-chain aldehydes arising from lipoprotein oxidation,
can induce transcriptional activation of the VCAM-1 gene mediated in part by
NF-κB.
Cancer
h e incidence of cancer increases with age in humans and in laboratory animals
alike, and AMs are involved in the various aspects of cancer. VCAM-1, for
example, has been suggested as a regulator of ovarian cancer peritoneal metastasis
(Slack-Davis et al. 2009). VCAM-1 expression was observed by Slack-Davis and