Nutrition and immunity in the elderly: modification of

immune responses with nutritional treatments1’3

Briino M Lesoiird

ABSTRACT Nutrition has a strong influence on the immune PHYSIOLOGIC AGING OF THE IMMUNE SYSTEM

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systeni of the elderly. Aging induces dysregulation of the immune
system. mainly as a result of changes in cell-mediated immunity. Several articles have reviewed the effects of aging on the
Aging is associated with changes to the equilibrium of peripheral
immune system (2-4, 9, 10). Briefly. aging has been shown to
T and B lymphocyte subsets. such as decreases in the ratios of induce low and less adaptable immune responses compared
mature to immature, naive to memory. T helper I subset (TH I ) to with those found in young adults. the changes being related
TH2. and CD5- to CD5+ cells. As a consequence. cell-mediated mainly to modifications of cell-mediated immunity.
immune responses are weaker and neither cell-mediated nor hu-
moral responses are as well adapted to the antigen stimulus. Cell-mediated immunity
Undernutrition. common in aged populations. also induces lower
Peripheral blood lymphocyte counts usually decrease with
immune responses. particularly in cell-mediated immunity. Pro-
age (Table 1). In healthy elderly people, this decline represents
tein-energy malnutrition is associated with decreased lymphocyte
only 10-15% oflymphocyte counts (5. 1 1, 12). In contrast with
proliferation. reduced cytokine release. and lower antibody re-
small changes in total lymphocyte count. there are important
spOnsC to vaccines. Micronutnient deficits. namely of zinc. sele-
modifications in T lymphocyte subsets in aged people ( 1 1 . 13).
nium, and vitamin B-6, all of which are prevalent in aged popu-
Aging has been associated with an increased number of imma-
lations, have the same influence on immune responses. Because
tune T lymphocytes (CD2+CD3-) along with a simultaneous
aging and malnutrition exert cumulative influences on immune
rise in natural killer (NK) cells (8. 1 3-1 5). Aging has been also
responses. many elderly people have poor cell-mediated immune
characterized by an increase of memory T lymphocytes (CD45
responses and are thereftre at a high risk of infection. Nutritional
RO) together with a decrease in the number of virgin or na#{239}ve
therapy may improve immune responses of elderly patients with
T lymphocytes (CD45 RA) (13. 16); however. these changes
protein-energy malnutrition. Supplementation with high pharma-
were observed mostly in young adults and not elders (16) and
cologic doses ofa single nutrient (zinc or vitamin E) may be useful
were related more to immune training than to aging.
for improving immune responses of self-sufficient elderly people
Changes in T helper ratios are also observed in aging: these
living at home. Therefore. nutritional deficiency must he treated in
modifications have been related to increases in the T helper 2
the elderly to reduce infectious risk and possibly slow the aging
subset (TH2) ( I 7, 18) with a parallel decrease in the TH 1
process. Am J Cliii Nutr I 997 :66:478S-84S.
subset (4, 13, 17). Note that these subsets were not quantified
with use of membrane markers because such markers have not
INTRODUCTION yet been characterized. The lymphocyte subsets were quanti-
fied by measuring interleukin (IL) secretions related to each
Immune responses are well known to fail with aging ( 1 ). It subset. Thus, in these early studies, IL-4, IL-S. and IL-6 were
is now thought that this failure is related more to immune measured to quantify the TH2 subset and IL-2 and interferon y
dysregulation (2) than to a general age-related decrease in for the THI subset. Such TH1-TH2 switches have been re-
immune responses as described previously (1. 3). Moreover. ported in diseases when important antigen pressure occurs, as
changes in immune response are not observed in all individuals in AIDS (acquired immunodeficiency syndrome) (19), and are
and when observed are less important (4, 5) than those initially probably related to antigen exposures during life.
described ( 1 . 3) in studies of healthy elderly persons (as de- All studies reported low reactivity of peripheral blood T
fined by the Senieur protocol) (6). Studies in healthy elderly lymphocytes in vitro after lectine (5, 7, 20, 21) or antigenic
persons showed that many modifications in immune responses
reported previously as being related to aging per se may in fact
From the Laboratoire d’Irnmunologie du vieillisseiiient, Facult#{233}de
be associated with pathologic conditions (7, 8). Undernutrition
M#{233}decine Piti#{233}-Salp#{233}tri#{232}re.
Paris. and Unite de M#{233}decine Nutritionnelle,
appears to be one of the main factors that can induce low
H#{244}pitalCharles Foix. Ivry sur Seine. France.
immune responses in aged individuals (5, 8). 1 discuss the
2 Presented at the symposium Nutritioti. Immunity. and Infection. held in
influence of nutritional deficit. regardless of cause. on immune Madrid, October 24-25. 1994.
response in aged people and also present a comprehensive Address reprint requests to BM Lesourd. Laboratoire d’Imrnunologie
physiologic view of nutritional influences on immune re- du vieillissement. Facult#{233}de M#{233}decine Piti#{233}-Salp#{233}tri#{232}re.
105. Boulevard de
sponses and health status of the aged. I’h#{244}pital. 75013 Paris. France.

478S An, J Cliii Nuir 1997:66:478S-84S. Printed in USA. 1997 American Society for Clitiical Nutrition
 NUTRITION AND IMMUNITY IN THE ELDERLY 479S

TABLE 1
Reciprocal influences of aging and protein-energy malnutrition (PEM) in the elderly: comparison of healthy adults and elderly selected with the
Senieur protocol with mildly undernourished elderly’

Healthy adults Healthy elderly Elderly with PEM

(a SO) (a 40) (a - 50)

Age (y 34.3 ± 13.7 78.7 7.4 78.4 9.3

Serum albumin (gIL) 43.3 ± 2.7 42.1 ± 2.8 31.4 t 3.7
T lymphocyte subsets ( X l09/L
Total count 2.190 ± 0.330 1.940 ± 0.51(1 1.450 0.560
CD3+ 1.855 ± 0.305 1.47(1 t 0.325 0.980 ± 0.425
CD2 +CD3 - 0. 105 ± 0.085 0.285 ± 0. 140 0.4 10 0.270
CDS7+ 0.155 ± 0.105 0.350 ± 0.250 0.520 0.220
CD4 + I . I9(1 ± 0.220 I .085 ± 0.285 0.680 ± 0.270

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CD8+ 0.610 ± 0.180 0.515 ± 0.25(1 0.425 t 0.280
CD4S RA+ 0.895 :t 0.530 0.425 ± 0.430 0.540 0.380
CD45 RO+ 0.785 ± 0.380 1.095 ± 0.280 0.650 0.310
Cytokine release
From lymphocytes. IL-2 (.tg/L 1.6 0.25 1.5 ± 0.35 0.84 t 0.23
From lymphocytes. IL-6 (.tg/L) I .3 ± 0. 1 S I .9 ± 0.30 0.74 t 0.28
From monocytes. IL- I ( l0 UIL)2 I 8.4 ± I 0. 1 1 3. I I I .4 4.2 t 4.8
T cell proliferation
WithPHA(I j.g/l0’cells) l()4±25 98t31 S427
With PPD antigen (10 g/l06 cells) 3(1 ± 14 25 IS 12 12

‘ Senieur protocol defined in reference 6. IL. interleukin: PHA. phytohemagglutinin: PPD. purified protein-derivated.
2 1 U = 10 gIL.

stimulation (22. 23). These decreased responses were measured with age. This might suggest an increased antibody response in
either by using a T cell proliferation assay (20-22) or by testing aging people.
the ability of lymphocytes to release IL-2 after stimulation (8. Although in general immunoglobulin concentrations in-
24. 25). In fact, several studies showed that immature T cells crease with age, specific antibody responses have been shown
(CD2 +CD3 - ) with the NK phenotype ( 15) or memory T cells to decrease with age in mice (32) and humans (22, 33). Previ-
with the CD45 RO phenotype (26) are less reactive than mature ous studies showed that after primary immunization (22. 33).
(CD3 + ) or naive (CD45 RA) T lymphocytes. Therefore, the antibody responses of aged individuals are characterized by
lower responses (ie, lower proliferation and lower IL-2 release) lower, slower, and shorter responses than those observed in
observed in aged humans and animals are probably the conse- young subjects (22); likewise, secondary responses are of a
quence of changes in T lymphocyte subsets with age. whatever shorter duration in elderly people (34).
the cause of these modifications [ie, whether decline of thymus Furthermore, the quality of specific antibodies is affected by
function causing T cell immaturity (5. 8) or antigenic activation age. Thus, antibodies produced after antigenic challenge have
inducing memory T cells (18, 19)J. a lower affinity for antigens and a narrower spectrum in aged
It can be concluded from these results that the capacity of than in young adults (32. 35). Although specific antibody
peripheral blood T lymphocytes to multiply in response to a responses decline with age. as mentioned above, autoantibody
stimulus is lower in the elderly than in younger individuals concentrations (36. 37) have been observed to increase with
and that these changes are responsible for the lower age and to be associated with lower specific antibody responses
cell-mediated immune- responses observed in aged people (38. 39). Such modification may be related to subtle changes in
(3-5). In fact, a depletion of cell-mediated immunity has B cell subpopulations. such as increases of CD5+ cells (2).
been pointed out both in vivo (5. 27) and in vitro (3-5. 7. 9. which are mostly involved in autoantibody production (40).
10, 28). Nevertheless, if IL-2 release decreases with age, Such changes have also been related to an increase of anti-
other cytokines are more intensively released in aged ani- idiotype antibodies, observed in mice (41) and in humans (39),
mals ( I 7) and humans ( 1 8). Thus, changes in cell-mediated which may block the production of specific antibodies. Anti-
immunity with age are now considered to be more a dys- idiotype antibodies are produced any time specific antibody
regulation phenomenon (2. 4. 13) than a decline of immune production is stimulated and reflect the antigenic stimulus.
responses. Increases in anti-idiotype antibodies with age may thus reflect
the cumulative effect of antigen exposure throughout life (41).
Humoral immunity Specific antibody responses are altered with aging. Repeated
Aging is overall not an important factor in changing humoral antigen exposure throughout life may be responsible fir the
immunity indexes. B cell subsets as well as B cell proliferation lower specific and higher nonspecific (auto- or anti-idiotype
do not decline in the elderly (5). However, concentrations of antibody or both) productions observed in aged individuals.
some immunoglobulins (eg, IgA and IgG) (5, 29, 30) as well as This effect also resembles a dysregulation more than a decrease
of monoclonal antibodies (3 1) have been shown to be increased in antibody production.
480S LESOURD

EFFECT OF PROTEIN-ENERGY MALNUTRITION ON humans with PEM (5 1 , 52). IL- 1 , in association with other
IMMUNE RESPONSES IN AGING PEOPLE monokines such as tumor necrosis factor a, IL-6, transforming
growth factor , IL-8. or IL- 1 1 . represents the central cone of
It is well known that infections are more common in under- all inflammatory syndromes (see Figure 1 in references 53 and
nourished than in well-nourished persons (42). This fact has
54). Therefore, PEM can modify the clinical symptoms of
been related to depletions in the immune system observed with inflammation in undernourished elderly individuals: for exam-
malnutrition (42, 43). There is a substantial drop in immune
ple, there is a low release of IL-I in undernourished elderly
responses both in undernourished and in aged but well-noun-
people during infection and although these patients are really
ished animals (44) and humans (5, 8, 45, 46). Both protein-
infected, in some no signs of fever are shown (52). This clinical
energy malnutrition (PEM) and aging exert cumulative effects
situation could lead to misdiagnosis and hence delays in treat-
on immune responses. inducing a sharp decline in immunity in
ment. This is why inflammatory syndromes have a long evo-
aged animals (44) or humans (I 1-13. 45-47) with low protein
lution period in elderly patients. Furthermore, low releases of
intakes. cytokines are also responsible for decreasing the mobilization

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of nutritional body reserves (55, 56), leading to an insufficient
Cell-mediated immunity
nutrient supply for lymphocytes and hence to deteriorating
Even apparently healthy and self-sufficient elderly people defense mechanisms.
can suffer from PEM, resulting in low peripheral blood CD3+
cell concentrations (Table 1) (1 1, 13, 45, 46). This result is
Humoral immunity
linked to a reduced CD4+ subset. In contrast, elderly people
who do not suffer from PEM have decreases in the CD8+ Antibody responses are also lowered in the undernourished
subset only (8, 13, 47). The subsequent decrease in the CD3+ elderly population. In earlier works, seroconversion rates after
subset caused by PEM is associated with simultaneous in- administration of tetanus toxoid (57) or influenza vaccine ( I 2,
creases in the CD2+CD3- subset that expresses the NK 58) were shown to be lower in elderly people suffering from
(CD57) phenotype (5, 8, 1 1 , 47). Because the effects of PEM malnutrition (Table 2). About 75% of vaccine unresponsive-
and aging on immune response are cumulative. PEM-associ- ness in hospitalized elderly patients is apparently related to
ated variations in immune function are especially significant in undernutrition (unpublished data, 1997). After vaccine shots,
the elderly (8. 45). Increases in immature CD2+CD3- T cell not only are antibody levels lowered in aged people suffering
subsets were observed in both healthy and well-nourished from malnutrition, but antibody affinity is also reduced (59).
elderly people. although low serum folate concentrations were Therefore, it can be suggested that vaccines in undernourished
found in these subjects (8). On the other hand, in malnourished elderly persons induce a lower level of protection than in
aged people, alterations in T lymphocyte subsets were shown well-nourished persons.
together with lower T lymphocyte proliferation and IL-2 re-
lease. compared with healthy aged people without any nutri-
Summary
tional inipairment ( I I , 1 3, 45, 47, 48). The damage from these
changes is strongly related to the extent of the albumin de- PEM leads to severe immunodeficiency in the elderly pop-
crease in elderly patients suffering from PEM (48). Malnutri- ulation, affecting not only specific immunity (B and T lym-
tion-related damage has physiologic consequences. In fact, it phocytes) but also nonspecific immunity (polymorphonuclear
has been reported that undernourished aged subjects are more cells and monocytes). PEM patients release fewer monokines,
likely to get pulmonary infections ( 1 2, 42, 49). Furthermore, which leads to reduced stimulation of lymphocytes, the func-
when this type of infection occurs. it further impairs the im- tions of which are already diminished. PEM patients are there-
munodeficiency already established (5. 49, 50). Thus, in many fore unable to raise their immune reactions to efficacy. As a
pulmonany-infected elderly individuals, CD4+ concentrations consequence, to stimulate specific immune responses at a suf-
have been reported to be as low as those found in patients with ficient level, the body expresses long-term acute-phase re-
AIDS (< 0.4 x l0#{176}
CD4+IL) (5. 50). sponses. This effect is even more pronounced in aged people
PEM induces not only low lymphocyte counts and functions because mobilization of body nutrient stores is less effective
but also low polymorphonuclear (44) and monocyte (51, 52) (55. 56) and also appears in individuals whose metabolism is
functions: for example IL- 1 cytokine release is decreased in lessened (60, 61).

TABLE 2
Comparison of individuals protected for influenza aniong hospitalized elderly patients in relation to initial influenza antibodies and albumin
concentrations

Percent protected: day 0 Percent protected: day 30

(antibody titer 4W (atitibody titer 40) Pence nt protected’

Albumin (g/L) Chili Philippines Chili Philippines Chili Philippines

C/

> 39 (‘1 = 57) 29.8 61.4 78.9 91.2 70.0 77.5

39 < albumin < 35 (a = 52) 30.8 48.1 71.2 82.7 58.4 66.7
< 35 (a = 24) 37.5 41.7 45.0 60.0 8.8 31.4

, Individuals in whom influenza antibodies were raised to protecting levels (antibody titer 40) after influenza vaccination.
 NUTRITION AND IMMUNITY IN THE ELDERLY 48 1 S

MICRONUTRIENT DEFICITS AND IMMUNE IL-2 release, and CD3+ subset were improved with this treat-
RESPONSES IN AGED PEOPLE ment when the micronutnient cocktail was given fir I y to
elderly people living at home. The positive immune effect was
Nutrient deficiencies are often associated and PEM is always associated with increased concentrations of micronutnients and
associated with micronutnient deficits. Immunodeficiency has thus the elimination of any micronutnient subdeficiencies and.
been reported in humans as well as in animals with micronu- more importantly, to a lower rate of infection during the
trient deficits (62-66). Lack of micronutrients such as zinc (46, supplementation year. This study highlights the significance of
64, 65) and selenium (66) and of vitamins including folic acid micronutrients in aging-related immunodeficiency.
(67), vitamin B-6 (68), and vitamin E (69) can induce a Although several studies showed previously that single-nu-
decrease in immune indexes. All of these micronutnient deficits tnient supplementation is an efficient way to restore immune
are common in the elderly (62, 63), generally in association responses in the elderly. supplementation in these studies was
with PEM. often at therapeutic levels (10-30 times the RDA). This im-
Zinc has been studied extensively in the elderly and is used proved efficiency has been shown for supplementation with
here as an example. Zinc deficiency is usually observed in zinc (74, 75) and vitamin E (79, 80). Zinc supplementation

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PEM (senic zinc is transported by albumin), although it has also reverses age-related T cell deficiency. partly by restoring thy-
been reported in 30-40% of home-dwelling elderly people with mic hormone (thymulin) function (81. 82). Such an effect.
no signs of PEM (46). Zinc deficiency could be related to many which sometimes is found with RDA doses. is associated with
causes, such as insufficient intakes, lower intestinal absorption, clinical improvement at all ages, with growth recovery in
or increased renal excretion associated with kidney failure or a infants (83), decreased opportunistic infection rates in AIDS
high diuretic consumption (70, 7 1 ), in summary, all the patho- patients (84), and nutritional recovery in the elderly (85. The
logic situations often observed in the elderly (72). Zinc is a effects of high doses of vitamin E on immune responses are
trace element of major importance for cell proliferation. In fact, proposed to be related to the antioxidant activity of this vitamin
zinc is a cofactor for many enzymes involved in cell division but no clinical effects have been reported. Therefore. nutri-
(70); furthermore, zinc is a cofactor of thymulin, a thymic tional supplementation acquires much interest because it can
hormone involved in thymocyte proliferation (thymulin is ac- restore defense mechanisms.
tive only when bounded to zinc) (71). Zinc is also a cofacton for
enzymes involved in cell membrane activation, such as
Humoral immunity
ATPase, which induces membrane fluidity (70. 71, 73). Zinc
Nutritional supplementation has also been shown to he ef-
deficits are associated with low immune responses as measured
by peripheral blood lymphocyte counts. T lymphocyte prolif- fective in restoring response to vaccines in undernourished
elderly people (12. 58. 59, 77, 86-88). Antibody responses of
eration, T cell IL-2 release, or T lymphocyte cytotoxicity (65.
70. 73). The significance of zinc on immune responses is aging. malnourished subjects can be raised when complete,
ready-to-use canned food (4(X)-5(X) kcal/d, on 1673-2092 kJ/d)
emphasized by the effect of zinc therapy. which increases
is used as a supplement ( I 2. 59. 77. 86). Supplementation could
immune responses in elderly people (46, 70. 73-75).
be recommended before vaccine shots (59. 77). Although these
studies showed effects of nutritional supplementation. food
REFEEDING EFFECTS ON IMMUNE RESPONSES IN intake was not controlled. Several studies have been performed
MALNOURISHED AGED PEOPLE to explore the effect of supplementation when food intake is
taken into account and measured ( 12, 87. 88). In one of these
Several studies have shown that nefeeding is an efficient way
studies, the effect of supplementation was quantified in elderly
to restore, at least partially, damaged immune responses in
patients who consumed low borderline intakes and did not
undernourished elderly patients.
show any inflammatory processes ( 12). The supplemented

Cell-mediated immunity group received 2580 kJ/d in addition to their usual intake of’
7280 ± 14(X) kJ/d. Antibody responses were quicker after
A 400-500-kcal/d ( I 673-2092-kJ/d) supplement is sufficient
tetanus toxoid shots in patients who had taken the supplement.
for improving some cell-mediated immune indexes that are
showing a positive effect even in elderly patients with low
lowered in elderly patients suffering from malnutrition. Im-
borderline intakes (Figure 1).
provement in cell-mediated immunity has been shown for T
In another study, yogurt (3 units of I 25 mg yogurt/d) was
cell proliferation as well as for delayed hypersensitivity (76,
used as a supplement (88). Some of the immunologic indexes
77). This effect has been observed with commercial, complete,
tested improved, but only during the supplementation period.
ready-to-use canned food containing at least one-third of all
although food intake was low ( 1500 kcal/d. or 6276 kJ/d). This
macro- and micronutrient recommended dietary allowances
study highlighted the importance of one nutrient: calcium.
(RDAs): there is no information available. however, on the
Further studies should investigate different macno- or micro-
major nutrients related to that improvement. In these studies, nutrients to find out which could be the most important in
total food intake was not measured and this is why the food
relation to the improvement of immune responses in the
intake necessary for an effect is still unknown. Despite these
elderly.
limitations, it can be concluded that the effect produced on the
immune system lasts only as long as the supplementation
period (77). CONCLUSION
Another study showed a similar effect by using only a
micronutrient cocktail. in which each micronutrient was be- The effects of aging on the immune system were initially
tween one and three times the RDA (78). T cell proliferation, described as reductions in immune responses. mainly in cell-
482S LESOURD

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