Age-related changes of apoptotic cell death in human lymphocytes

Abstract

Apoptosis seems to be involved in irnmunosenescence associated with aging. Moreover, in lymphocytes (PBL) of patients with Akheimer's disease, an increased susceptibirity to the apoprotic pathway has been described possibly due to impaired protection o f oxidative stress. Accordingly. it seemed to be of particular interest to investigate the contribution of normal aging to the susceptibility from human lymphocytes 20 programmed cell death. We coiild show that PBL from elderly individuals (>60 years) accumuIate apoptosing cells to a significant higher extent in spontaneous and activation-induced cell death compared to younger controls (<35 years). Treatment with the oxidative Stressor 2-deoxy-D-ribose or with agonistic-CD95-antibody pronounced this effect even more implicating a higher sensitivity to reactive oxygen species and a higher functionril CD95 expression, respectively. In addition, expression of the activation markerc HLA-DR and CD95 was significantly increased in CD3 "-cells of aged subjects, while expression of CD25 did not seem to be affected by age.Expression of Bcl-2 was increased in aging and comlated with the number o f apoptotic cells.Kqwordv. &in& Apoptosis: 1,yrnphocytes; Oxidativc stress; dctivation markers; Bcl-2 Programmed cell death (PCD) or apoptosis is of particular interest in aging, as it is thought X o play an irnportant role in various age-related degenerative diseases. Apoptosis of white bIood cells could be one reason for the decrease of the total number of leukocytes and the decrease of the immune response with aging related Z o Cancer, infections, and autoirnmune disorders [3]. Several changes in lymphocytes have been observed related to aging: diminished synthesis of g r o~h and survive factos 146,511, impaired intracellular calcium regulation [18], different surface malecule expression 1431, and defects of signal transdi~ction [36]. Some of these pathological changes are additionally altered in patients witl~ Alzheimer's disease (AD), but are not present in vascular dementia [13][14][15]171. In order to differentiate common and divergent mechanisms of an enhanced susceptibility of lymphocytes to apoptosis in aging and sporadic AD, we investigated in detail the molecular basis of enhanced apoptosis in aged human lymphocytes. Oxidative Stress increases with aging and ltads to enhanced cellular damage (e.g. Iipidperoxidation, protein oxidation, DNA damage (for review see ref.[IO]). In addition, reactive axygen species (ROS) can trigger cells to undergo pragrammed cell death and can act as second rnessenger by influencing transcription factors like NF-KB and AP-I. Increased oxidative stress and decreased ability to cope with ROS could ampliQ apoptotic cell death in aging lymphocytes. BcI-2 acts in an antioxidative and antiapoptotic way and can interfcre with the apoptotic pathway 17,471.One oF the best known and characterized surface receptors related to PCD in lymphocytes is ApollFas (CD95), a rnernber of the himor necrosis factor (W) superfamily. Stimulation of this recep...

Age-related impairment of human T lymphocytes’ activation: specific differences between CD4+ and CD8+ subsets

“…In an earlier study, we found increased basal apoptosis of lymphocytes derived from aged individuals (Schindowski et al, 2000). The enhanced incidence of apoptosis might be associated with the loss of CD3 + cells.…”

“…Moreover, other theories explain declined cellular activity within aging by increased oxidative stress (Guyton et al, 1998). Previous studies on lymphocytes revealed an increase of reactive oxygen species (ROS) in aged subjects (Schindowski et al, 2000) or elevated by-products caused by ROS (e.g. lipidperoxidation (Hendricks and Heidrick, 1998), oxidized proteins (Stadtman, 1992;Berlett and Stadtman, 1997) and DNA-damage (Wei et al, 1998)).…”

Bcl-2 activates a programme of premature senescence in human carcinoma cells

“…Is Bcl-2 normally involved in the control of cellular replicative senescence? The accumulation of Bcl-2 protein, which has been reported in several different cell types during senescence, both in vitro [45] and in vivo [46,47], may support an involvement of Bcl-2 in normal aging processes. However, the activation of a premature senescence programme by Bcl-2, which we describe in two different carcinoma cell lines, has never been observed in normal cells.…”

Aging and asthma – changes in CD45RA, CD29 and CD95 T cells subsets

“…10,11 Several environmental factors and health conditions have a recognised capacity for eliciting cell activation into memory and effectors populations and to trigger apoptosis with varying impact on successful aging. 12 In allergic asthma there is a continuous stimulation of TL by several aeroallergens, which can lead to a decrease in naive T cells. A decrease in apoptosis can also help to sustain the airway inflammation that characterises the disease.…”