Previously, we have demonstrated age-associated alterations in transmembrane signaling.
One of the most reproducible alterations found in the immune response with aging is
the decrease of lymphocyte proliferation on stimulation with various different mitogens.
Here, we confirm that proliferative responses to stimulation with phytohaemagglutin
(PHA), recombinant human IL-2, or anti-CD3 monoclonal antibody are all greater in
the young (20-25 years) than old (60-87 years) population. We attempted to modulate
the proliferative response using various agents acting at different levels of transmembrane
signaling (pertussis toxin, cholera toxin, isoproterenol, PMA, Ca ionophore A23187),
as well as at the level of the lymphocyte plasma membrane (methyl-beta-cyclodextrin,
MBCD), or by using antioxidant vitamins (Vitamin E or C). None of these agents was
able to restore effectively the proliferative response of lymphocytes from the aged
to the level of young subjects. Even the combination of A23187 and PMA acting directly
on calcium metabolism and protein kinase C activity was insufficient to restore the
decreased mitogenic capacity of T cells from elderly subjects. Cyclodextrin, which
decreases the cholesterol content of the membrane, increased the proliferative response
of lymphocytes of elderly subjects, but not to the level of the young. Vitamin E had
a very strong inhibitory effect on lymphocyte stimulation in both the age groups,
except in combination with MBCD in T cells of the elderly, while Vitamin C had no
significant modulatory effect. MAPK ERK and p38 activation was found to be decreased
with aging in T cells after anti-CD3 mAb stimulation. Vitamin E but not Vitamin C
strongly inhibited MAPK ERK or p38 activation. The direct activation of certain molecules
or the modulation of the cholesterol content of the membrane seems to be effective
immunomodulatory interventions with aging.
