Micronutrient status, immune response and infectious disease in elderly of less developed countries

Introduction

The world's population, especially in less developed countries, is expected to continue expanding. This growth is occurring together with a demographic transition due to increase in lifespan, and decrease in mortality and fertility. As a result, the number of people aged above 60 years in less developed countries is expected to increase from a current 8% to 20% in 2050, with the group above 80 years growing almost five fold¹. When using country median age as an indicator of ageing, the 2006 Revision of the U.N. World Population Prospects shows that the overall world population will age (Figure 1) and that this shift will occur mainly in developing countries. But, even though lifespan has increased, quality of life has not improved for this age group², leading to unhealthy ageing and increased morbidity. As it has been eloquently expressed on the 1995 State of World Health, “For most of the people in the world today every step in life, from infancy to old age, is taken under the twin shadows of poverty and inequity, and under the double burden of suffering and disease. For many, the prospect of a longer life may seem more like a punishment than a prize.” A primordial objective is not only to increase lifespan but to achieve successful ageing, which is defined as minimizing the time between the onset of illness and death³.

Figure 1.

Demographic transition towards and older population (United Nations, Population Division, 1999).

Elderly in the less developed world play an important role in society and in their country's economy⁴. However, they are vulnerable to malnutrition and suffer from infectious diseases. Additionally, in the past years many elderly from less developed countries have experienced an increase in chronic diseases as a consequence of the double burden of malnutrition^5,6. The increase of infectious and non-communicable disease within this expanding population has translated into poor quality of life and an increased burden on the healthcare systems of their countries.

Subclinical levels of micronutrients have been associated with impaired immune function in people above the age of 60⁷, and it has been found that micronutrient supplementation and improved nutrition can enhance immune function^8,9. It is important, however, that more information is obtained on regional micronutrient status and the benefits a nutrition intervention might have. Such studies on elderly populations in the developing world are limited. Often data obtained from developed countries is applied to less developed countries, or has been extrapolated from younger age groups within the same country. Many aspects of populations in developed countries are not applicable to groups in less developed countries. Also, changes in health, physiology, and immune function during ageing make younger groups an inappropriate model for an older group.

In this review we will describe age-associated changes in immune response, summarize the impact of micronutrients on immune status in the elderly, assess the current micronutrient status of the elderly in less developed countries and its relation to their immune response, and review current interventions to determine what they teach us for improving the health outcomes of this growing population, as well as the obstacles we need to overcome.

Ageing and immunity

Both innate and acquired immunity weaken with age even in “healthy” elderly¹⁰. Age-related changes detrimental to the immune system include thymic involution, poor response to vaccinations, impaired response to evolving pathogens and newly encountered antigens, increased vulnerability to infection, increased autoimmunity, and inflammation^11–13.

The most widely studied cells of innate immunity with respect to ageing are macrophages. Some, but not all studies have shown that macrophage chemotaxis, phagocytosis, cytokine production and bone marrow population are compromised with age¹⁴. Macrophages are part of the defense barrier in the skin; they detect pathogens and defend the body against bacteria¹⁴. Because skin is affected with ageing, its efficiency as a protective barrier declines, and along with it macrophage function is altered. This change leads to increased colonization of bacteria and yeast on the skin and on mucosal surfaces¹⁴. Wound repair is also affected with ageing partly due to delayed macrophage infiltration and function. This causes delayed symptom manifestation and diagnosis of infection, which exacerbates disease¹⁴. Therefore, in general, macrophage ability to fight infection is impaired and there is deregulation of the molecules they produce. For example, production of prostaglandin E2, an inflammatory molecule which has been shown to suppress T cell function in aged¹⁵, as well as contribute to several chronic diseases associated with aging such as cardiovascular and inflammatory diseases, is increased with age^16,17.

Many aspects related to changes in other innate immune system cells such as neutrophils, eosinophils, mast cells and NK cells remain undiscovered or controversial. However, it is known that neutrophil phagocytosis and superoxide (O2−) and hydrogen peroxide (H2O2) production is impaired, and mast cell number seems to decrease in the skin¹⁸. Also, eosinophil function becomes impaired, leading to increased responses to allergens, explaining in part the exacerbation of asthma with older age¹⁸. Dendritic cell (DC) function decreases with age¹⁹ and chemotaxis may be compromised¹⁸ but it is not clear whether the number of DCs decreases¹¹.

The adaptive immune system, whose main players are T and B cells, is widely modified with ageing. Even though peripheral B cell number and secreted immunoglobulin levels stay constant with age there is impaired naïve B cell production¹¹, less affinity from antibodies to antigen, and more autoantibodies produced²⁰. These changes may reduce the response to newly encountered antigens¹⁹.

It has been established that that T cell decline is the main cause of immune senescence^3,19. There is reduced number of naïve T cells, and an expansion of memory T cells¹¹. This imbalance results in part from thymic involution and the expansion of memory T cells as a result of persistent or latent pathogens¹³. The imbalance leads to a decreased response to new antigens, such as new strains of influenza¹¹. Additionally, CD4 T helper cell number and function declines, and CD8 cytotoxic effector T lymphocytes (CTLs) have reduced intensity in their response against influenza vaccine and less interferon-gamma (IFNγ) production during viral infections¹⁹. Influenza is the fifth cause of death in people older than 50 years¹⁹. This age group is a target for vaccination campaigns, but influenza virus vaccines have only 30–40% efficacy in the elderly^11,13.

In addition to age-associated immunological changes which predispose the elderly to higher incidence of infectious diseases, a recent report by Gay et al.²¹ showed that passage of an avirulent coxsackie B3 virus (COXB3-0), which normally does not cause morbidity and mortality in young mice, through old host resulted in several mutations in the virus which increased its virulence, transforming into a morbidity and mortality causing virus for the young mice. These results indicate that in addition to immunological changes, increased viral virulence in the aged host could contribute to their higher susceptibility to infection. Given that Beck et al.²² have shown that micronutrient deficiencies such as those of selenium and vitamin E also increase viral virulence, and there is a high prevalence of nutritional deficiencies in less developed countries and an increasing number of older people in these countries, these findings could have significant public health implications worldwide and emphasize the need to address nutritional deficiencies in the elderly of less developed countries.

Micronutrient status, ageing and immunity

Adequate nutritional status is essential for efficient immune function. Investigating this relationship and its relevance to ageing is of great importance for the health of elderly and for disease prevention⁸. Many postulate that improvements of nutritional status in elderly populations will enhance their immune system^8,20. In turn, this would lead to enhanced nutritional status by preventing consequences of infectious disease, such as nutrient malabsorption, nutrient and energy store loss, and reduced appetite³. There is a large body of evidence on the potential benefits micronutrient enhancement can have for the ageing immune system. However, much of this evidence comes from the developed world and has yet to be extended to less developed countries.

There are several comprehensive reviews of micronutrient supplementation studies in the elderly^3,23. Single nutrient supplementation studies have shown improvement in the immune response of the elderly. These nutrients include vitamin B6^24,25, vitamin C^26,27, vitamin E^9,28,29 and zinc^30,31. Also, there may be a role of vitamin D in age-related deregulation of the immune response in elderly^32,33. However, more studies relate to this topic are needed. Additionally, there are studies supporting that certain micronutrients, such as antioxidants, be given as a mixture so that they work synergistically and to prevent an imbalance that may lead to prooxidant production³⁴. However, such evidence of supplementation in the elderly remains controversial. A systematic review by Stephen and Avenell³⁵ showed that there was no significant effect of micronutrient mixture supplements in the elderly. But, subgroup analysis within that study showed that elderly undernourished at baseline and consuming supplements for 6 months experienced the greatest benefit. A high proportion of elderly in developed countries take multi-vitamins, which may bias results of an intervention trial. Therefore the lack of the effect observed following micronutrient supplementation in developed countries might not be applicable to less developed countries.

A randomized controlled trial in which Girodon et al.³⁶ supplemented institutionalized elderly with zinc, selenium, and vitamins A, C, and E for two years showed significant improvement in antibody production in response to influenza vaccine in groups receiving single supplements or combinations thereof. Also in this study a correlation was observed between zinc and selenium supplementation and reduction of respiratory infections. This study suggests that elderly vaccine response can be enhanced through micronutrient supplementation, which would not only prevent disease and malnutrition but also reduce the economic strain on the health care system by decreasing costs associated with hospitalization.

The nutritional status and presence of other diseases could influence the impact of nutritional intervention on immune response and resistance to infection in elderly. For example, Graat³⁴ showed that supplementing a group of elderly individuals from the Netherlands replete with vitamin C and E with a 200 mg daily of vitamin E had no effect on infectious disease outcomes. On the other hand, a vitamin E trial by Meydani et al.³⁷ showed that supplementing nursing home residents with 200 IU per day of vitamin E reduced upper respiratory tract infections, such as the common cold. Differences in disease status, genetic background, as well as study design and documentation of infection could have attributed to the observed³⁸. Further analysis from the study by Meydani et al.³⁹ also found that low serum zinc levels in this population correlated with higher incidence and duration of pneumonia. A recent study also showed that genetic variation in cytokine genes can influence the impact of vitamin E supplementation on cytokine production in elderly⁴⁰.

Finally, research on probiotic supplementation to prevent or reduce infection is being developed and offers potential for immune system enhancement. Probiotics help maintain immunologic balance in the mucosal sites of the body, protect against pathogens, and it has been suggested that they help restore impaired innate immunity in the mucosal epithelia⁴¹. Long-term daily supplementation of 479 healthy adults (18–67 years old) with vitamins and minerals, with or without probiotics, did not show a difference in the incidence of common colds; but, shorter duration of colds, decreased severity of symptoms, and enhanced T cell responses were observed⁴². Another study showed that elderly supplemented with probiotic supplements had higher antibody titers after influenza vaccination than those given a placebo, indicating the potential of probiotics in enhancing response to vaccine in the elderly⁴³. Since the “indigenous microbiota” population in the intestinal mucosa changes with age⁴¹, probiotic supplementation, together with micronutrient supplementation may have a positive impact on elderly immunity. In summary, the studies described above conducted in developed countries indicate that micronutrient and other dietary interventions could be of benefit to the elderly of less developed countries in protecting the elderly against infection and other immune/inflammation related diseases¹¹, minimizing the number of years in a person's life during which he or she will suffer from recurring disease (Figure 2) and allowing healthy ageing.

Figure 2.

Hypothetical effect of micronutrient status assessment and nutritional interventions in elderly from developing countries (adapted from Dr. Jose Ordovas, JM-USDA HNRC at Tufts University).

Micronutrient status, immune response and infectious diseases in elderly from less developed countries

The most prevalent and targeted causes of malnutrition worldwide are protein energy malnutrition and vitamin A, iodine, iron, and zinc deficiency. Data on micronutrient status in less developed countries is abundant for vulnerable groups, particularly children and pregnant women, but scarce in the elderly. The reasons for less developed country elderly vulnerability to malnutrition include poor diet, food insecurity, lack of public health measures and low allocation of government funds to the health care system⁴⁴, resulting in higher incidence of diseases. In many less developed nations consumption of foods from animal origin is very low due to inaccessibility and/or religious practices, limiting micronutrient consumption. This scenario also translates into low protein consumption, which has been shown to impair the immune system in the elderly⁴⁵. In addition, many regions have high consumption of phytates, lowering further the absorption of minerals in a group that already has limited access to nutrients. All these factors lead to higher incidence of communicable diseases and, due to the nutrition transition and consumption of low quality (empty calories) food, to obesity and chronic disease as well⁶.

In order to target appropriate micronutrient interventions and develop effective public health measures more detailed nutritional data is needed from less developed nations. Nutritional status, even though generally impaired in poor elderly populations, differs greatly between regions. The recommended micronutrient dosages to be used in supplementation in less developed countries, listed elsewhere⁴⁶, divide individuals into three age groups: 1 to 3 years, 4 to 13 years, and >14 years. Elderly are grouped together with adults, but due to their impaired nutrient absorption and intake, not to mention disease status, they may require different doses for certain nutrients.

Table 1 summarizes studies that have reported micronutrient status in less developed country elderly and the relationships between micronutrients and immune response and infection. From this limited data it is clear that micronutrient deficiencies vary greatly from region to region, even within the same country. Even though vitamins C and E play an important role in immune function and in the prevention of chronic diseases due to their antioxidant properties very little data has been acquired from elderly in less developed countries on these micronutrients (Table 1). Hamer et al. reported that 92.4% of elderly Ecuadorians were deficient in vitamin C and that plasma vitamin C and zinc levels correlated with impaired immune cell's ability to produce IFNγ. A little more is known about B vitamins, which are important in the development of chronic disease, anemia, and cognition impairment, and are involved in a wide array of cellular functions, including immune response. Vitamin B12 deficiency is common in the elderly both in developed and less developed countries. In the less developed world, however, there is higher prevalence and it starts earlier in life^5,47 because of low dietary intake and other environment factors. Helicobacter pylori infection has been identified as one of the causes for poor vitamin B12 absorption. There is evidence that probiotic supplementation can help displace harmful bacteria and repopulate harmless or beneficial intestinal flora. Parasitic infections are common in less developed countries both among children and the elderly. Hamer et al. found that most elderly Ecuadorians in their study had parasites⁵. In addition, as shown in table 1 other B vitamin deficiencies are also prevalent. For example, riboflavin deficiency has been found in several countries in the past few decades.

Table 1.

Studies on micronutrient status in less developed countries

Location	Reference	Age (years)	Sample Size	Study Description	Findings - Micronutrient Status	Immune Response Findings
Central Guatemala	Boisvert et al, 1983	50+	433	Cross-sectional. Dietary assessment and riboflavin status.	Riboflavin deficiency prevalency was 50–76%. Levels correlated with milk intake. Small intervention trial revealed strong correlation between riboflavin status and dietary intake.	Study did not look at immune response
Bangkok, Thailand	Prayurahong et al, 1993	NA (elderly)	147	Cross-sectional Study. Hematological data.	15% of subjects had anemia, 21% were folic acid deficient, and 7% were B12 insufficient.	Study did not look at immune response
Zimbabwe	Allain et al, 1997	65+	278	Cross-sectional Study. Hemoglobin, folate and B12 levels in rural and urban elderly.	Anemia seen in 23% of subjects, 30% had low folate level, and 13% had low serum B12 level. Folate was lower in urban subjects and B12 was lower in rural subjects.	Study did not look at immune response
Chile	Olivares et al, 2000	60+	274	Cross-sectional Study. Anthropometric measurements and biochemical measures of iron, copper, folate, vitamins B12 and A and C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR).	5% men and 4% women were anemic. Abnormal serum retinol was seen in 14% of men and 16% of women. Folate deficiency was 50% in men and 33% in women. B12 deficiency seen in 51% of men and 31% of women. Almost no iron and copper deficiencies.	10% subjects had inflammation (high ESR and CRP values, and high white blood cell count). They had higher prevalence of anemia (22% men and 32% women).
Chile	Bunout et al, 2001	70+	98	Randomized controlled trial; lasted 18 months. Micronutrient supplement with or without exercise.	Compliance with supplement was 48%. Supplemented, and supplemented + exercise maintained weight, lean mass, bone mineral density, serum cholesterol, and had greater muscle strength.	Study did not look at immune response
Chile	Hirsch et al, 2002	70+	108	Prospective study. Six months after folic acid fortification started determine effect on folic acid and B12 status and plasma homocysteine	Folic acid increased, plasma homocysteine decreased, and B12 stayed the same. Authors recommend elderly B12 supplementation.	Study did not look at immune response
Chile	Bunout et al, 2004	70+	60	Randomized controlled trial. Micronutrient (vitamin E, B12, folate), probiotic and protein supplementation, and placebo.	Micronutrient status was not reported in this study.	Response to influenza and pneumococcal vaccination. They observe enhanced NK cell activity. There was no change in IL-2 production. Subjects on supplement reported less infections, measured by scheduled hospital visits.
Cape Town, South Africa	Charlton et al, 2001	68.9 (SD=5.7)	148	Cross-sectional Study. 24-hr recall and anthropological measurements.	About one third had intake <67% RDA. Low intakes of calcium, vitamin D, zinc, and B6. Low fruit and vegetable consumption. Over half of women and 18% men were obese.	Study did not look at immune response
Beirut, Lebanon	Sibai et al, 2003	65+	200	Cross-sectional. Questionnaires, anthropometric measurements, hematological and biochemical analyses	Deficiencies in zinc, magnesium, alpha-tocopherol, and vit A, D and B6 were observed in both institutionalized and free-living elderly. Also, they were anemic and had low albumin levels.	Study did not look at immune response
Cape Town, South Africa	Charlton et al, 2005	72.7 (SD=8.3)	285	Cross-sectional. 24-hr recall, plasma micronutrient levels, anthropometric measurements.	Micronutrient levels (Thiamin, riboflavin, niacin, vit B6, folate, panthotenate, biotin, vit C, calcium, iron, magnesium, phosphorus, zinc, copper, and selenium) were inversely related to added sugar intake. Sugar has a nutrient-diluting effect.	Study did not look at immune response
Taiwan	Cheng et al, 2005	65+	2373	Crossectional Study (Elderly NAHSIT). Plasma retinol and tocopherol measurements.	Low prevalence of plasma retinol or a-tocopherol deficiency.	Study did not look at immune response
Taiwan	Wang and Shaw, 2005	65+	2354	Crossectional Study (Elderly NAHSIT). Plasma iron measurements.	Low prevalence of iron deficiency or iron deficiency anemia in men and women. Some subjects had elevated iron stores.	Study did not look at immune response
Taiwan	Wang et al, 2005	65+	1911 for dietary intake; 2225 for plasma Mg levels	Crossectional Study (Elderly NAHSIT). 24-hr recall and biochemical measurements of magnesium.	Dietary magnesium intake was about 70% of DRI, and 8–9% had low plasma magnesium levels. Magnesium levels and diabetes inversely related.	Study did not look at immune response
Taiwan	Yang et al, 2005	65+	2379	Crossectional Study (Elderly NAHSIT). Biochemical measurements of thiamin and riboflavin.	17% men and 14% women were thiamin deficient. 6.6% men and 4% women were riboflavin deficient. A large proportion (>11% for thiamin and >20% for riboflavin) were marginally deficient for both vitamins.	Study did not look at immune response
Quito, Ecuador	Sempertegui et al, 2006	74.3 (SD=6.9)	145	Cross-sectional. Nutritional assessment through 24-hr recall, DTH, biochemichal and anthropometric measurements.	50% of subjects had low plasma B12, Zn, and Fe. About 30% had low B6, and 19% were low in folate and vitamin D	Low DTH response. In previous 6 months, 54% and 21% had at least one episode of RI or diarrhoea, respectively
Quito, Ecuador	Hamer et al, 2008	74.4 (SD=6.4)	352	Cross-sectional.CRONOS Questionnaires, anthopometric, blood micronutrient and immuno assays.	Deficiencies for vitamins C, D, B6; zinc and folate.	Plasma Vit C associated with IFNg production. Zinc associated with IFNg and IL2 production. Micronutrient deficiency and poor immune response and burden of RI like pneumonia and common cold. Micronutrient deficiency associated with history of recent infection

DTH = delayed type hypersensitivity

RI = respiratory infection

NA = Not available

PEM = Protein Energy Malnutrition

CRONOS = Cross Cultural Research on the Nutrition of Older Subjects

Iron Deficiency Anemia (IDA) affects about one quarter of the world's population⁴⁸. The causes for this deficiency in elderly include low iron intake, high levels of dietary phytates and low animal food consumption, as well as atrophic gastritis, intestinal atrophies and in some instances Helicobacter pylori infection⁴⁹. National data on elderly anemia prevalence is missing from many countries. According to Deitchler et al.⁵⁰ only three countries out of 12 countries studied, Indonesia, Laos, and the Philippines, have recorded anemia prevalence in the elderly and found it to be greater than 30%. In a study by Hamer et al.⁵ it was found that 39% of the elderly Ecuadorians in the study had serum iron below the reference range. Furthermore, they found that iron status correlated with immune cell ability to produce interleukin-2 (IL-2).

Several organizations and governments estimate micronutrient status in specific regions, but direct measurements are scarce. For example, McLean et al.⁴⁸ gathered global and regional data from the WHO Vitamin and Mineral Nutrition Information System for 1993–2005 and determined anemia prevalence in different vulnerable groups based either on actual data or estimations. Data on the elderly were unavailable in almost every country, so only global estimations were made. It was determined that 24%, or 163 million, of elderly were suffering from iron deficiency anemia, with the highest proportion being in low-income countries.

Zinc deficiency is prevalent in elderly of both developed and less developed countries. Hamer et al.⁵ reported that close to 50% of elderly Ecuadorians had low serum zinc level and low serum zinc levels correlated with low IL-2 and INFg levels. Interestingly, Meydani et al.³⁹ reported that 30% of nursing home residents in US also had low serum zinc levels which were associated with higher incidence of pneumonia. Results from study by Hamer et al. indicated that elderly Ecuadorians had much higher prevalence of micronutrient deficiencies compared to those living in US and that corresponded with their lower immune response compared to those living in US. For example, zinc deficiency was found to be two to three times (depending on whether independently living or NH residents) higher in elderly Ecuadorians compared to those in US, and their delayed type hypersensitivity response (a measure of cell-mediated immunity) was half that of their counterparts in US. Hamer et al. also showed that elderly Ecuadorians have higher incidence of infectious disease than those living in US and that a significant correlation exist between micronutrient deficiency and infection in these elderly. While several factors including sanitation could contribute to higher incidence of infection in elderly Ecuadorians compared to US elderly, these data point to micronutrient deficiencies as an important contributor.

Summary and Conclusions

In summary, the elderly population is increasing worldwide and is suffering from the double burden of disease, i.e. both chronic and infectious diseases, and as such face significantly more health problems compared to other age groups. Many factors contribute to higher susceptibility of infection in elderly (Figure 3), chief among them are age-related immunological changes. In addition recent data suggest that the environment of old host might increase viral virulence and the morbidity and mortality caused by them. The limited data available suggest that the elderly in less developed countries suffer from high prevalence of several micronutrient deficiencies. Furthermore, these reports indicate that the prevalence and type of micronutrient deficiencies differ by region, and are correlated with low immune response and high incidence of infection. Micronutrients are needed for immune response and their deficiency not only impairs the immune response, but could also increase viral virulence by causing mutations in the virus. Thus, the combined impact of immunological defects, increase viral virulence in the aged, and presence of micronutrient deficiencies in the aged not only puts the elderly of less developed countries at high risk of infection and morbidity and mortality from them, but could pose a public health problem for all age groups by helping spread of more virulent viral species. Therefore, there is an urgent need to address the nutritional problems of elderly of less developed countries so that effective intervention strategies can be devised. Region-specific studies to determine micronutrient status are needed so that cost-effective supplementation strategies could be proposed, and for those countries in which specific deficiencies have already been described, studies are needed to demonstrate the efficacy of specific micronutrient supplementation to improve immune response and decrease infectious diseases.

Figure 3.

Holistic view of factors that influence the immune system.

Even though much data remains to be gathered with respect to micronutrient status in elderly from less developed countries, especially as it pertains to immune response, some initiatives have been taken to improve elderly health and quality of life. In response to the demographic transition and the economic strain of elderly disease, Chile's government developed a program to distribute a micronutrient mix fortified with vitamins and minerals to low-income elderly⁵¹. It would be interesting to determine whether this program has lead to disease prevention and improvement of Chilean low-income elderly nutritional status and quality of life.

In conclusion, there is an urgent need for acquiring more data on nutritional status of elderly in less developed countries and implementing specific interventions. Generation of this information will improve nutritional status of elderly in a cost-effective manner, which in turn could result in reduction of both infectious and chronic diseases, increase health span, improved quality of life in this age group and significant saving of health care resources in these countries. Furthermore, improving the nutritional status of elderly in less developed countries could reduce the global burden of infectious disease.