Introduction
Purpose
The United Nations
World Population Prospects projects the number of persons aged 80 years + will triple from 137 million in 2017 to 425 million in 2050 [
1]. The prevalence of chronic diseases, such as cancer, cardiovascular, and neurodegenerative diseases, is anticipated to rise along with this elderly population [
2].
Nutrition contributes to overall health and improves treatment response for chronic diseases (i.e., immune response, mobility, cognitive function, healing) [
2,
3]. A compromised health status can increase hospital length of stay and promote the development of comorbidities, contributing to additional costs of $13,350–$19,530 per hospitalization and $77,000 per year of care associated with poor nutrition status [
4].
Aging is associated with an overall decline in physiological functions that contribute to inadequate nutritional status (i.e., decreased metabolic rate and gastric secretions, decreased sensory functions in oral cavity, increased use of medications, changes in overall body mass and electrolyte distribution) [
2‐
5]. The cumulative effects of aging and micronutrient deficiencies in the older persons result in frailty, cognitive decline, poor immune response, cardiovascular disease, cancer, and other factors of morbidity [
2,
6,
7]. On the other hand, the widespread use of dietary supplements (52% of adults in the USA report the use of at least one supplement product) has been reported to be of no benefit for some nutrients and could have deleterious consequences in this age group [
8‐
11].
The purpose of this review is to update knowledge and briefly discuss the role and new findings of vitamins A, B12, and D, calcium, iron, and folate on morbidity and quality of life during aging, especially considering the increased life expectancy and the costs of care of this age group.
Approach
A literature review of the periods 2012 to 2018 in older people aged 65+ years, focusing on vitamin A, vitamin B
12, vitamin D, calcium, iron, and folate, was performed in MEDLINE and Google Scholar as these micronutrients are found to significantly affect the aging process [
9‐
11]. Although the United Nations agreed cutoff is 60+ years to refer to the older population [
12], developed world countries accept the age of 65+ years as the working definition of elderly [
13]. Because most published studies have been done in developed nations, 65+ years of age was used for this review. The lists of references from selected articles were also searched.
The review focused on the consequences of inappropriate consumption of some vitamins and minerals—by excess or deficit—on the aging process itself and on the health and wellbeing of this age group, highlighting interactions between nutrients, research needs, and controversial points, when applicable. The risk of excessive intakes of vitamins and minerals is a topic that is getting more and more relevance in recent studies, due to the consequences for health on all age groups. For each nutrient, a brief description on the function and role in aging, the recommended nutrient intakes (RNI) [
14], and the tolerable upper intake levels (UL) [
15] were included (Table
1).
Table 1
Recommended nutrient intakes (RNI) and tolerable upper intake levels (UL) for selected micronutrients in the elderly (65+ years)
Vitamin A | 600 μg/day | 3000 μg/day |
Vitamin B12 | 2.4 μg/day | ND |
Folate | 400 μg/day | 1000 μg/day |
Vitamin D | 15 μg/day | 50 μg/day |
Calcium | 1300 mg/day | 2500 mg/day |
Iron | Based on diet availability (15, 12, 10, 5%) | |
Male | 9, 11, 14, 27 mg/day | 45 mg/day |
Female | 8, 9, 11, 23 mg/day | 45 mg/day |
Findings
Vitamin A
Importance of Vitamin A in Aging
Vitamin A has several important roles in the aging process: mainly immune function and oxidative processes. Deficiency is associated with defective immune response to infection. All-trans retinoic acid (RA), a common form of active vitamin A, plays a role in immune homeostasis through regulating cell homing and differentiation. During times of infection or autoimmune disease, it activates T cell responses [
16]. Emerging research is focusing on the effects of vitamin A enhancing T cell responses to cancer, infection, intestinal inflammation, and immune-mediated diseases in humans including autoimmune disease—all associated with aging [
16].
Interaction Between Nutrients
Vitamin A, a fat-soluble vitamin, is absorbed with vitamin D. Thus, serum retinol should always be assessed in the presence of vitamin D supplementation [
23]. New research has found that retinoic acid and vitamin D calcitriol combined influence proliferation and differentiation of osteoblasts [
30]. An increase in PPARγ2 expression was observed following retinoic acid administration, whereas a decrease was observed following calcitriol administration [
30]. Additionally, cumulative serum retinol and zinc levels among older persons may help in high-frequency hearing loss [
31]. Similarly, zinc supplementation in individuals aged 70–85 years increased vitamin A levels proportionately with zinc [
32].
Gaps in Research—Further Research
Leukocyte telomere length (LTL) is a biomarker of the aging process. These repetitive sequences of DNA at the ends of chromosomes serve to protect the ends of DNA strands and are associated with risk of chronic disease. High oxidative stress can lead to DNA strand breaks, shortening telomeres. Several serum carotenoids, including β-carotene, β-cryptoxanthin, lutein, and zeaxanthin), were found to be associated with LTL. Vitamin A roles in immune function, inflammation, regulation of gene expression, and epigenetic modification, help maintain LTL [
33•]. More research is needed to understand the association between vitamin A, LTL, and the potential use of this association during the aging process.
The potential for exacerbating an already serious public health problem, with intakes of vitamin A currently considered safe, indicates further research into this matter is needed.
Vitamin B12 and Folate
Importance of Vitamin B12 and Folate in Aging
Vitamin B
12 and folate are associated with preventing chronic diseases associated with aging through the methylation of homocysteine [
34]. This is a vital process preventing amyloid and tau protein accumulation which can cause cognitive decline [
34]. The genetic polymorphism in the MTHFR 677TT gene is hypothesized to be a main contributor to metabolism in aging processes [
35•]. Elevated homocysteine and lower vitamin B levels impact the immune system, causing increased inflammation and antioxidant damage which catalyze physiological aging in all systems [
35•].
Interaction Between Nutrients
As the older persons have increased consumption of gastric acid inhibitors, they are at increased risk of vitamin B
12 deficiency due to the lack of vitamin B
12 absorption. Calcium supplementation has been found to positively affect the association between gastric acid inhibitors and vitamin B
12 deficiency [
49].
Gaps in Research—Further Research
It is still unknown to what extent B vitamins involved in one-carbon metabolism can affect DNA methylation throughout the life cycle. Some studies have found that long-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, including those implicated in developmental processes. Furthermore, more research is needed on the effect of both folate and B12 on cognitive function, CVD, and bone health as they relate to aging. Public health conclusions in regard to folate and vitamin B12 point to fortification of foods, but safe upper level intake of folic acid and its interaction with vitamin B12 needs to be further researched. This is especially urgent in regard to the potentially positive role excess folate contributes to promoting colorectal cancer.
Iron
Importance in Aging
Iron is an essential functional component of vital metabolic functions such as oxygen transport, oxidative energy production, inactivation of harmful oxygen radicals, and DNA synthesis. It has a nutrigenomic effect in the central nervous system as a cofactor for oxidative phosphorylation, neurotransmitter production, nitric oxide metabolism, and oxygen transport, playing an important role in neuroprotection and neuronal activities [
50].
Studies reveal iron is essential to maintain immune and antioxidant function during aging [
51]. Iron status becomes impaired in situations that involve chronic inflammation, such as obesity or aging [
50,
52] and malnutrition exacerbates these effects of inflammation [
53•]. Inflammation affects hepcidin, a peptide hormone that regulates iron homeostasis [
53•].
Anemia and iron deficiency are two of the most prevalent disorders worldwide, affecting people in all regions and ages, including older persons. Iron overload, although usually associated to pathological conditions, also has important consequences on health and could be of relevance during aging [
54].
Interaction Between Nutrients
Vitamin C might increase the absorption of dietary iron by up to 10% and calcium decreases iron absorption. Therefore, if both are needed, it is advised to take iron and calcium hours apart [
69,
70]. Additionally, if taken without food, large doses of iron supplements impair the absorption of zinc [
50].
Gaps in Research—Further Research
The diagnosis of iron deficiency anemia is highly controversial. Based on the differences in iron absorption and chronic inflammation, as well as the prevalence of comorbidities, the diagnosis of iron deficiency and iron excess in the older persons needs specific review. It may also be appropriate for future diagnosis standards of iron deficiency to be based on differences in iron absorption, age, gender, and race.
Vitamin D and Calcium
Importance of Vitamin in Aging
Vitamin D intake and absorption drastically decreases with age due to decreased sunlight exposure, nutrient intake, fat absorption, and conversion of vitamin D to its active form [
2]. In regard to aging, vitamin D is associated with cognition, depression, cancer, and cardiovascular disease [
10,
24,
71]. Vitamin D stimulates clearance and phagocytosis by macrophages, protecting immune cells against apoptosis by regulating both extranuclear protein functions and gene expression signaling [
72].
Calcium and vitamin D interact to effect vasculature, lipid metabolism, and neuromodulation. Strongly influenced by age, the efficiency of calcium absorption from the gastrointestinal tract decreases significantly after age 60 in both sexes: with those aged 70 years and older absorbing approximately one-third less calcium than do younger adults. Women are at an even greater risk of decreased calcium because of a decreased fractional calcium absorption after menopause, estrogens acceleration on bone loss, and increased urinary calcium losses [
73,
74].
Interactions Between Nutrients
Vitamin D forms the basis of calcium’s homeostatic mechanism. Calcium and vitamin D interact through regulated feedback and are dependent on each other for maintenance of appropriate levels. Vitamin D insufficiency may result in a relative hypocalcemia and high serum PTH concentrations, which alone has been linked to poor health outcomes [
73]. This secondary hyperparathyroidism can be attenuated by the administration of vitamin D supplements. Calcium can compete or interfere with the absorption of iron, zinc, and magnesium [
92] and must be addressed if older persons are at risk of these deficiencies.
Gaps in Research—Further Research
Due to vitamin D’s unique activation processes (requiring sun exposure), accurate levels of RNI are hard to discern and are widely debated [
73]. Those that are institutionalized, homebound, have limited sun exposure, dark skin, or malabsorption are at increased risk for vitamin D deficiency and recommended to consume more with a goal of achieving levels of ≥ 30 ng/mL [
93]. A cohesive definition of vitamin D insufficiency must be addressed. Vitamin D thresholds for deficiency and excess need to be reviewed for all age groups, since the signs and symptoms of deficiency are not always related to the current cutoff points.
Most research relating calcium and aging has been in conjunction with vitamin D. Yet, according to recent findings, calcium may be a critical nutrient in neurocognitive protection and bone health. Recent reviews have not found a clear link between many of the recommended intake levels of vitamin D or calcium with improvements in health outcomes and more research is needed to determine accurate thresholds for the elderly. Additionally, more robust research is needed to determine causation of vitamin D on health outcomes and dose-dependent effects of both vitamin D and calcium on bone health [
9,
71,
82].
Limitations/Implications
This review did not include all micronutrients contributing to the aging process and health outcomes in the elderly (i.e., thiamin, riboflavin, magnesium, selenium, zinc, or vitamin C) which will be important for further reviews as current evidence reveals inadequate intakes in the elderly population and consequential harm [
77•].
Overall, there are insufficient studies on the elderly age group and on different outcomes by gender. Within the older persons, studies must sub-classify and subgroup cohorts. For example, a recent systematic review on all health outcomes associated with vitamin D contained very limited information on individuals older than 70 years. It would be interesting to consider subgrouping ages in the old people group, especially for some nutrients and functions that are not necessarily the same for 70- or 80-year-old individuals.
Due to the brevity of this review, details and limitations of each review presented were not mentioned. Populations studied, sample size, and overlapping age ranges may not be generalizable to all elderly. In addition, the detail we were able to provide on each study was limited.
As the use of supplements increases and prevention is emphasized, the application of these micronutrients should be adequately studied for safe treatment recommendations in the elderly population. Low dietary intakes and all micronutrient deficiencies mentioned in this review are associated with functional decline, decreased quality of life, and increased healthcare costs. However, over supplementation is also dangerous and more studies on the subclinical effects and interactions with other nutrients are needed.
Seeking to understand the definitive thresholds of the different vitamins and minerals on their association with health outcomes, both in deficiencies (such as vitamin D) and excess (such as vitamin A and calcium), is important for setting clinical guidelines and policies. There is a need for more robust and focused research to determine micronutrient effects and application to medical conditions related to aging, such as neurocognitive disorders, cardiovascular disease, and cancer.
Finally, it is difficult to assess the value of nutrition interventions since most clinical trials do not assess the costs acquired from morbidity and mortality secondary to malnutrition. More studies are needed to determine the link of nutritional deficiencies with hospital length of stay, preventable healthcare use, and costs.
Conclusion
A literature review of the periods 2012 to 2017, focusing on vitamin A, vitamin B12, vitamin D, calcium, iron, and folate, was completed and these micronutrients are found to significantly affect the aging process. Micronutrient inadequacies are a common and avoidable contributor to decreased quality of life in the elderly. Further research is needed to determine adequate intakes, including appropriate thresholds for health outcomes and safety from over supplementation for this population.
Compliance with Ethical Standards
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.