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Aging of the immune system
Medical Hypotheses 18: 157-161, 1985
AGING OF THE IMMUNE SYSTEM
Philip Rosen, Hasbrouck Laboratory, University of Massachusetts, Amherst, MA 01003 ABSTRACT
A review of the literature shows that the thymus is the major reason for aging of the immune system. A graph of the mouse thymus mass is linear with age after puberty. However, T cell function is determined by thymic hormone factors and serum thymic factors. The net result is that T cell function is so affected that there is a deficit in T cell responsiveness. For humans a graph of 1-I (I is immunological efficiency) versus age is a straight line on a semi-log plot. The slope of the line is about the same as the incidence of class I cancer incidence vs. age.
INTRODUCTION
In a previous paper (11, a study was made of the various theories of aging and the importance of metabolic activity was shown. This led to a free radical theory of aging. A dimensionless number(lT was discovered, where .Iis the Gompertz constant and T was the maximum lifespan of a species.
In a recent work (2) Walford reviewed the various theories of aging and emphasized the free radical theory and the aging of the immune system. In this paper I would like to review the present state of our knowledge of the aging of the immune system. THE THYMUS
According to Makinodan (31, the most important organ in the immune system with respect to effects of aging is the thymus gland. Figure one shows how the thymus gland of the mouse changes its mass after the initial drop from the maximum at about puberty. It is seen that the percentage of the maximum mass follows a straight line as a function of age. This type of behavior is typical of the aging of organs. Respiration being linear with time leads to organs decaying in a linear (4) or near linear manner with age (2). In humans I do not have complete data but the mass of the thymus is 45% of maximum at puberty (4) Also starting with a value of 37 grams at maximum; 157
between ages 65 - 70 years the mass is 6 grams or 16.2% of the maximum (5). Taking the mouse to have a maximum life span of about 41 weeks (l), the thymus is 15% of the maximum at age 32.5 weeks. This last figure is comparable to the value for humans whose maximum life span is about 100 years
40
0
I
I
I
IO
20
30
Age 1 months
Fig. 1:
d
40
)
The weight of the thymus of the mouse vs. age (expressed as % of maximum weight).
THE THYMIC HORMONES
More important than the mass of the thymus are the hormone factors (5) such as thymosin, thymic humoral factor and serum thymic factors like: factor of thymic serum (FTS), serum factor (SF) and thymopoietin. These hormone factors regulate the formation of subpopulations of T cells. The serum thymosin-like factors drop off rapidly between ages 25 and 45 and the thymus dependent immunity drops off after age 20. The diseases of aging like cancer, autoimmune diseases and infectious diseases rise exponentially after age 20.
According to Makinodan (3), the total number of T cells does not decrease appreciably with age. However, there is a decline in T-cell function. Helper T cells are also affected. There is a deficit in T cell responsiveness.
158
Since involution of the thymus precedes decline in T cell function, it is suspected that thymic involution results in a decreased capacity of the system to generate functional T cells (7). Hirokawa and Makenodan (8) transplanted thymus lobes from mice 1 day to 33 months old into young adult T cell deprived recipients and assessed kinetically the emergence of T cells. They found that the ability of the thymus tissue to influence the maturation of precursor cells into functional T cells decreases with age.
CANCER
For humans figure 2 shows age associated changes in relative immunologic activity as reflected in serum isoantibody concentration. As a semi-log plot I have plotted 1-I (I is immunological efficiency) versus age. When I compare the slope in figure 2 with that of the incidence of Class 1 tumors versus age (9), the slopes are nearly the same.
for men log % total incidence = 0.031 (age) - 1.15
(1)
for women log % total incidence = 0.027 (age) - 0.897
(2)
log (1 - I> = 0.026 (age> - 2.17
(3)
The major point I wish to make is that the aging of the immune system is the major factor in dependence of cancer incidence on age.
AUTOIMMUNE DISEASE
Patients with autoimmune disease and immune complex disease can be helped by treatments with thymosin (6). It is suggested that there is a restoration of a subpopulation of thymus activated cells called suppressor T cells. One would suppose that either suppressor T cell function is affected or that their number is reduced (6) (10).
ENDOCRINE SYSTEM EFFECTS
The effects of various hormones on the thymus are important in discussing aging. A positive action is exerted by somatotropic hormone, thyroxin, and insulin. A depression of immune function occurs with corticosteroids, gonadotropin, progesteroids, and testosterone. Hormonal balance is necessary for homeostasis. An excellent example of reproductive death occurs in the Pacific salmon (2) at spawning time when massive amounts of corticoid hormones are released into the blood stream. A similar situation occurs in the octupus (2). At a certain stage in life after the octopus mates its optic gland releases the 159
hormone overdose. Removal of the optic gland allows the octupus to live five times its normal life span.
10-l
n
I
I o-2 7
L
I
I
0
20
40
I
I
60
80
t
Fig 2:
(1 - I> expressed as a decimal vs. age t on a a semi-log plot.
CONCLUSION
In addition to the aging by free radical cell damage due to metabolism, one must consider the aging of the immune system. The major factors in immune senescence are the thymus hormone factors and serum thymic factors which are 160
responsible for the differentiation of T cells. Thymic involution and is responsible for age dependent decline in the ability of the system to generate functional T cells. Because T cell function is there are increases in death due to cancer, autoimmune disease and
precedes immune affected, infection.
REFERENCES
1.
Rosen P, Woodhead AD, and Thompson KH. The relationship between the Gompertz constant and maximum potential life span. Exp. Geront. 16: 131, 1981. 2. Walford RL. Maximum Life Span. W.W. Norton, New York, 1983. 3. Makinoden T. The thymus in ageing. p. 217 in Geriatric Endocrinology (Aging, Vol. 5) R.B. Greenblatt ed., Raven Press, New York, 1978. 4. Sinclair D. Human Growth After Birth, 3rd ed., Oxford Press, London, 1978. 5. Encyclopaedia Britannica, Enclopaedia Britannica, Inc., William Benton, ed. Chicago, 1961. 6. Goldstein AL, Thurman GB, Low TLK. Travers GE, and Rossio JL. Thymosin, the endocrine thymus and its role in the aging process. P 51 in Physiology and Cell Biology of Aging (Aging, Vol. 81, A Cherkin et al. eds. Raven Press, New York, 1979. 7. Kay MMB and Baker LS. Cell changes associated with declining immune function. p. 27 in Physiology and All Biology of Aging, (Aging, Vol. 8) 4. Cherkin et al., eds., Raven Press, New York, 1979. 8. Hirokawa K and Makinodan T. Thymic involution effect on T cell differentiation. J. Immunol. 114: 1659, 1975. 9. Dix D, Cohen P, and Flannery J. On the role of aging in cancer incidence. J. Theor. Biol. 83: 163, 1983. 10. Roitt IM. Essential Immunology. 3rd ed. Blackwell Scientific Publications, Oxford, 1977. 11. Fabris H. Body homeostatic mechanisms and aging of the immune system. p. 61 in CRC Handbook of Immunology in Aging, M.B.M. Kay and T. Makinodan eds. CRC Press, Boca Raton, Florida, 1981.
161
AGING OF THE IMMUNE SYSTEM
Philip Rosen, Hasbrouck Laboratory, University of Massachusetts, Amherst, MA 01003 ABSTRACT
A review of the literature shows that the thymus is the major reason for aging of the immune system. A graph of the mouse thymus mass is linear with age after puberty. However, T cell function is determined by thymic hormone factors and serum thymic factors. The net result is that T cell function is so affected that there is a deficit in T cell responsiveness. For humans a graph of 1-I (I is immunological efficiency) versus age is a straight line on a semi-log plot. The slope of the line is about the same as the incidence of class I cancer incidence vs. age.
INTRODUCTION
In a previous paper (11, a study was made of the various theories of aging and the importance of metabolic activity was shown. This led to a free radical theory of aging. A dimensionless number(lT was discovered, where .Iis the Gompertz constant and T was the maximum lifespan of a species.
In a recent work (2) Walford reviewed the various theories of aging and emphasized the free radical theory and the aging of the immune system. In this paper I would like to review the present state of our knowledge of the aging of the immune system. THE THYMUS
According to Makinodan (31, the most important organ in the immune system with respect to effects of aging is the thymus gland. Figure one shows how the thymus gland of the mouse changes its mass after the initial drop from the maximum at about puberty. It is seen that the percentage of the maximum mass follows a straight line as a function of age. This type of behavior is typical of the aging of organs. Respiration being linear with time leads to organs decaying in a linear (4) or near linear manner with age (2). In humans I do not have complete data but the mass of the thymus is 45% of maximum at puberty (4) Also starting with a value of 37 grams at maximum; 157
between ages 65 - 70 years the mass is 6 grams or 16.2% of the maximum (5). Taking the mouse to have a maximum life span of about 41 weeks (l), the thymus is 15% of the maximum at age 32.5 weeks. This last figure is comparable to the value for humans whose maximum life span is about 100 years
40
0
I
I
I
IO
20
30
Age 1 months
Fig. 1:
d
40
)
The weight of the thymus of the mouse vs. age (expressed as % of maximum weight).
THE THYMIC HORMONES
More important than the mass of the thymus are the hormone factors (5) such as thymosin, thymic humoral factor and serum thymic factors like: factor of thymic serum (FTS), serum factor (SF) and thymopoietin. These hormone factors regulate the formation of subpopulations of T cells. The serum thymosin-like factors drop off rapidly between ages 25 and 45 and the thymus dependent immunity drops off after age 20. The diseases of aging like cancer, autoimmune diseases and infectious diseases rise exponentially after age 20.
According to Makinodan (3), the total number of T cells does not decrease appreciably with age. However, there is a decline in T-cell function. Helper T cells are also affected. There is a deficit in T cell responsiveness.
158
Since involution of the thymus precedes decline in T cell function, it is suspected that thymic involution results in a decreased capacity of the system to generate functional T cells (7). Hirokawa and Makenodan (8) transplanted thymus lobes from mice 1 day to 33 months old into young adult T cell deprived recipients and assessed kinetically the emergence of T cells. They found that the ability of the thymus tissue to influence the maturation of precursor cells into functional T cells decreases with age.
CANCER
For humans figure 2 shows age associated changes in relative immunologic activity as reflected in serum isoantibody concentration. As a semi-log plot I have plotted 1-I (I is immunological efficiency) versus age. When I compare the slope in figure 2 with that of the incidence of Class 1 tumors versus age (9), the slopes are nearly the same.
for men log % total incidence = 0.031 (age) - 1.15
(1)
for women log % total incidence = 0.027 (age) - 0.897
(2)
log (1 - I> = 0.026 (age> - 2.17
(3)
The major point I wish to make is that the aging of the immune system is the major factor in dependence of cancer incidence on age.
AUTOIMMUNE DISEASE
Patients with autoimmune disease and immune complex disease can be helped by treatments with thymosin (6). It is suggested that there is a restoration of a subpopulation of thymus activated cells called suppressor T cells. One would suppose that either suppressor T cell function is affected or that their number is reduced (6) (10).
ENDOCRINE SYSTEM EFFECTS
The effects of various hormones on the thymus are important in discussing aging. A positive action is exerted by somatotropic hormone, thyroxin, and insulin. A depression of immune function occurs with corticosteroids, gonadotropin, progesteroids, and testosterone. Hormonal balance is necessary for homeostasis. An excellent example of reproductive death occurs in the Pacific salmon (2) at spawning time when massive amounts of corticoid hormones are released into the blood stream. A similar situation occurs in the octupus (2). At a certain stage in life after the octopus mates its optic gland releases the 159
hormone overdose. Removal of the optic gland allows the octupus to live five times its normal life span.
10-l
n
I
I o-2 7
L
I
I
0
20
40
I
I
60
80
t
Fig 2:
(1 - I> expressed as a decimal vs. age t on a a semi-log plot.
CONCLUSION
In addition to the aging by free radical cell damage due to metabolism, one must consider the aging of the immune system. The major factors in immune senescence are the thymus hormone factors and serum thymic factors which are 160
responsible for the differentiation of T cells. Thymic involution and is responsible for age dependent decline in the ability of the system to generate functional T cells. Because T cell function is there are increases in death due to cancer, autoimmune disease and
precedes immune affected, infection.
REFERENCES
1.
Rosen P, Woodhead AD, and Thompson KH. The relationship between the Gompertz constant and maximum potential life span. Exp. Geront. 16: 131, 1981. 2. Walford RL. Maximum Life Span. W.W. Norton, New York, 1983. 3. Makinoden T. The thymus in ageing. p. 217 in Geriatric Endocrinology (Aging, Vol. 5) R.B. Greenblatt ed., Raven Press, New York, 1978. 4. Sinclair D. Human Growth After Birth, 3rd ed., Oxford Press, London, 1978. 5. Encyclopaedia Britannica, Enclopaedia Britannica, Inc., William Benton, ed. Chicago, 1961. 6. Goldstein AL, Thurman GB, Low TLK. Travers GE, and Rossio JL. Thymosin, the endocrine thymus and its role in the aging process. P 51 in Physiology and Cell Biology of Aging (Aging, Vol. 81, A Cherkin et al. eds. Raven Press, New York, 1979. 7. Kay MMB and Baker LS. Cell changes associated with declining immune function. p. 27 in Physiology and All Biology of Aging, (Aging, Vol. 8) 4. Cherkin et al., eds., Raven Press, New York, 1979. 8. Hirokawa K and Makinodan T. Thymic involution effect on T cell differentiation. J. Immunol. 114: 1659, 1975. 9. Dix D, Cohen P, and Flannery J. On the role of aging in cancer incidence. J. Theor. Biol. 83: 163, 1983. 10. Roitt IM. Essential Immunology. 3rd ed. Blackwell Scientific Publications, Oxford, 1977. 11. Fabris H. Body homeostatic mechanisms and aging of the immune system. p. 61 in CRC Handbook of Immunology in Aging, M.B.M. Kay and T. Makinodan eds. CRC Press, Boca Raton, Florida, 1981.
161