Immunology: Animal Models

Normal aging is inevitably associated with an overall decline of functional performance of all tissues (systemic change). However, some individuals develop degenerative diseases with autoimmune characteristics, resulting in the aging of tissue-specific cells (organ-specific change).

Systemic change. Although the complex mechanisms of the primary processes of aging are unknown, many theories have been proposed. The most popular concern pertubations of biologic systems, such as neuroendocrine or immune systems, or of the genetic program, as well as phenomena such as somatic-cell mutation, error accumulation and repair, entropy, and cell loss. The maximum life span of mammals (the life span of the longest-lived survivors) shows marked variations among species. Figure 1 shows that the extent of skin aging, as determined by the pentosidine level in skin collagen, substantially increases with the maximum life span for each species. Yet, the progressive increase begins with the onset of immune senescence, i.e., dimunution of T lymphocyte function accompanying age-associated involution of thymus and coinciding with the decline of immune-system function. These observations indicate that the onset of both immune senescence and skin aging are not dependent on time, but are genetically programmed for each species.

Studies of animal models have also shown that epigenetic factors, i.e., exogenous (environmental) substances and influences, which may silence or enhance the activity of genes, can influence longevity of individuals and prevent systemic changes. Early caloric restriction significantly extends the life span, retards the aging rate, and delays immunologic, biologic, and pathologic changes. The immune system of long-lived mice matured more slowly and declined later in life when subjected to a life-extending, calorically restricted (but nutritionally adequate) diet.

Organ-specific change. Along with gradual systemic aging, some individuals exhibit an accelerated organ-specific aging known as degenerative diseases with autoimmune characteristics. These diseases may affect virtually any tissue, but most frequently affected are neural tissues (multiple sclerosis and presenile dementia), the cardiovascular system (atherosclerosis), synovial tissue (rheumatoid arthritis), and the pancreas (diabetes mellitus). Degenerative diseases may have different etiologies, but they have in common an accelerated aging of tissue-specific cells caused by an inappropriate relationship of the immune system toward self.

Figure 1 Maximum Lifespan, Immune Function, and Skin Aging Schematic. The correlation among maximum lifespan (solid line), immune system performance (blocks), and skin aging (dashed line) in various species. Immune system performance increases during childhood (ch), full immune competence (IC) is attained at the beginning of reproductive period (rp; 12 to 14 years of age in humans), and declines in aging individuals (ag) from the onset of the immune senescence (IS; 42 to 46 years of age in humans). Note that skin aging is not time-dependent, but accelerates with the onset of the immune senescence in a species-specific manner. SOURCE: Data obtained from the following sources: 1) Geokas M. C.; Lakatta E. G.; Makinodan T.; Timiras P. S. "The Aging Process." Annals of Internal Medicine 113 (1990): 455–466. 2) Klein J. Immunology: The Science of Self-Nonself Discrimination. New York: John Wiley & Sons, Inc., 1982. 3) Sell D. R.; Lane M. A.; Johnson W. A.; Masoro E. J.; Mock O. B.; Reiser K. M.; Fogarty J. F.; Cutler R. G.; Ingram D. K., et al. "Longevity and the Genetic Determination of Collagen Glycoxidation Kinetics in Mammalian Senescence." Proceedings of the National Academy of Science. 93 (1996): 485–490.

In normal individuals, the first organ affected by aging is the ovary. Ovarian aging is not only of major importance in its own right, but is also of interest for its relationship to the general biology of senescence. There is a striking correlation between the period at which an organ is present during early ontogeny and that organ's functional longevity (see Figure 2). For instance, the liver, which differentiates very early, can (in human beings) function for over one hundred years. However the ovary, which differentiates much later, does not function for more than a half of that period.

Animal models have shown that additional restriction of ovarian development in early ontogeny, for instance by injection of androgens during immune adaptation, results in the premature aging of the ovary. Hence, epigenetic (or, in certain individuals, inherited) restriction of organ development prior to the end of immune adaptation can result in the reduction of tissue's functional longevity.