Aging of the Immune System

The progression of age-related changes depends on the ability to repair biochemical damage and on the ability to generate precursors from stem cells and generate end cells from precursors. Throughout life, the immune system is dependent on processes of differentiation from precursors to functionally specialized lymphocytes of two types: committed thymus-derived (T) and bone marrow-derived (B) cells.

Because precursor cells replicate and their descendants differentiate to become mature cells, the immune system is profoundly affected by wear and tear of precursor cells and less by wear and tear of mature cells than are tissues such as muscle and brain. Therefore, to what extent do precursor cells lose their ability for self-renewal? There appears to be a correlation between the number of in vitro cell division of fibroblasts and age of donor.

Argument for a biological link between this type of in vitro and in vivo aging can be found in the reported correlation between average life span of different species and the number of in vitro divisions that their fibroblasts can undergo. Nevertheless, the effect of age on the in vivo capacity for self-renewal remains a controversial subject. It may depend on the developmental distance from the primitive stem cell.

The further the precursor cell differentiates toward a fully committed cell (end cell), the greater the probability that self-renewal declines. The polymorphism of these changes remains to be explored and may contribute to the resolution of contradictory results.

In early postnatal life, T cells acquire their functional specialization in the thymus. Involution of the thymus is a programmed feature of postnatal development and reaches completion in middle age (in humans, at about 50 yr of age). In men it occures at an earlier age than in women; hormonal controls can affect the rate of thymus regression.

The pituitary gland is implicated in some of the changes. Furthermore, the age-related decrease in the secretion of thymus hormones, such as thymulin, may be due to a decrease in synthesis of thyroxine, the thyroid hormone. Whether or not initiation of thymus regression is triggered by endocrine controls is not definitively established. Events in the thymus itself are multicentric, which results in different types of precursor cells, that is, precursors of suppressor cells for humoral and cell-mediated immunity age at different rates and even in different directions (one class decreases while another increases with age in some inbred mouse strains).

A decreasing supply of thymic peptides and cytokines may be pacemakers of the impact of involution on the immune response and contribute to the peripheral consequences of involution. The involution of the thymus initiates peripheral age-related changes in immune responsiveness during the second half of life. However, precursor cells, which leave the thymus, settle in spleen and lymph nodes and are sources for renewal of T-cell function in later life. Finally, the involution of the thymus affects peripheral function if or when the peripheral pools have exhausted their ability for self-renewal.

The general view on aging-progression, deduced from observations on humans, can be extended and confirmed in appropriate animal model systems, particularly with animals of different homogeneous genetic background (i.e., with strains of inbred mice).

The validity of extension from animal to humans depends on the validity of the assumptions that the factors involved in aging are common to all mammals. In fact, there is indirect evidence for this view. A positive correlation exists between life span and concentration in the liver of carotenoids, α-tocopherol, ceruloplasmin, and ascorbate; an inverse correlation is evident between life span and concentration of cytochrome, gluthathione transferase, and catalase.

It is, therefore, reasonable to conclude that aging of different mammals depends on similar processes and that it is legitimate to extrapolate from short-lived to long- lived mammals. In general, aging is apparently dramatic in some, but not all, compartments of the immune system. We shall briefly consider the polymorphism of some of the following cell populations:

1. T-suppressor capacity for antibody response;
2. T-suppressor capacity for cell-mediated immunity;
3. cytotoxic T cells (CTL);
4. В cells and T-cell helper capacity;
5. nonspecific killer (NK) and lymphocyte-activated killer (LAK) cells.