Mini ReviewCalcium metabolism and vitamin D in the extreme longevity
Introduction
Considering the fast increase of life expectancy worldwide and in the developing countries in particular, the maintenance of self-sufficiency is of extreme importance in the oldest olds. Among those able to reach the extreme limits of life, centenarians represent an example of successful aging, due probably to their genotypes and to peculiar neuro-immuno-endocrine mechanisms (Mariotti et al., 1992, Sansoni et al., 1993, Franceschi et al., 1995, Mari et al., 1996, De Benedictis et al., 1997, Baggio et al., 1998, Deiana et al., 1999, Fagnoni et al., 2000).
It is true that prevention of bone fragility fractures is of pivotal importance at all ages, but this is even more important in the oldest olds, since a fracture, especially of the hip, often means the permanent loss of walking ability, and of self-sufficiency (Passeri, 1991, Mariotti et al., 1992, Johnell and Kanis, 2006). Elderly subjects are at risk of fractures for several reasons: falls are of primary importance, but a relevant role is also played by loss of bone mass with subsequent reduction of bone strength (osteoporosis). Insufficient dietary intake of calcium, low physical activity, systemic diseases and medical treatments affecting bone, hormonal status, and finally, low circulating levels of vitamin D are all co-morbidity factors (Cooper et al., 1992, Rosen and Kiel, 1999, Martini and Passeri, 2000, Heaney, 2004, Sambrook and Cooper, 2006). The skeletal remodelling, consisting of a continuous process of bone resorption of the pre-existing bone followed by bone formation, remains active even after 80 years of age. However, it is evident a disequilibrium of these two processes, with a prevalence of bone resorption, especially in the elderly (Passeri, 1991, Marcus et al., 1995, Martini and Passeri, 2000, Sambrook et al., 2006). It has been demonstrated, above the age of 60 years, a clear prevalence of bone resorption, while bone formation is of varying extent, even if several metabolic parameters (e.g., serum osteocalcin) are also increased (Ross and Knowlton, 1998). Some changes characterizing aging at the cellular level, are due to a reduced numbers of fully functional cells, accompanied by impaired matrix production, cellular composition, and bone microenvironments, and altered responses to the environment (Carrington, 2005).
Nevertheless, bone remodelling is closely correlated with calcium exchange, and is strongly influenced by the actions of vitamin D (Burckhardt, 2002). As it is well known, calcium is an ion of fundamental importance for all living systems, and it has a great number of functions at both intra- and extra-cellular levels (e.g., blood coagulation, function of adhesive molecules, muscular contraction, second messenger functions in the cells, etc.) (Bringhurst, 1995). In bone, calcium is of basic importance for skeletal physical resistance and as a deposit from which the organism can mobilize calcium when needed. The extra-cellular concentration of Ca2+ ions is in the order of 10−3 M, while in the cellular cytoplasm is only around 10−6 M. Free cytoplasmatic Ca2+ may quickly and largely changes its concentration (up to 100 times), as a consequence of the binding of primary extra cellular messengers to the respective receptors on the membrane of the target cells. Among the fractions of the circulating calcium (bound to proteins: about 40%; complexed mainly with citrate and phosphate ions: about 10%; and the rest is ionized) (Bringhurst, 1995), the ionized fraction is the most important from a physiological point of view and it is maintained in a very narrow range by the combined effects of different hormones, in particular PTH, 1,25(OH)2D3 and calcitonin (Parfitt, 1993).
These are the main factors able to control the global balance of calcium in the body, by regulating the bi-directional calcium fluxes between the gastrointestinal system, kidneys, and bones, toward the extra cellular calcium pool (Bringhurst, 1995). Nevertheless, other hormonal factors, whose secretion is not directly regulated by calcium circulating levels, have a considerably importance in calcium exchanges and, eventually, for bone health: sexual steroids, thyroid hormones, glycocorticoids and growth hormone (GH) are the most important (Marcus et al., 1995, Raisz, 2005).
Section snippets
Calcium metabolism
Intestinal calcium absorption is determined by the amount of calcium present in the food and by the absorptive capabilities of the intestine itself, at the level of duodenum and upper part of the jejunum. When the amount of calcium introduced with diet is less than 200 mg/day, the net intestinal absorption is practically zero, since approximately the same quantity is daily secreted into gastrointestinal lumen, and lost with the feces. When dietary calcium is above 200 mg/day, the absorbed amount
The role of the vitamin D
The action of the vitamin D, especially the active form 1,25(OH)2D3, is of fundamental importance in most of the bone metabolic equilibrium processes. Vitamin D is a secosteroid synthesized in the skin starting from 7-dehydro-cholesterol: the UV light catalyzes this reaction, or it can also be introduced in the body orally or parenterally (Lund and DeLuca, 1969, Holick, 1995). Several factors may interfere with the skin-production of vitamin D: an increase in the melanin in the skin,
Vitamin D insufficiency
Hypovitaminosis D always causes a reduction of calcium intestinal absorption that induces a negative calcium balance. Hypocalcemia due to insufficient calcium absorption, induces an increment of PTH with also an increase of the synthesis of 1,25(OH)2D3. This induces resorption of calcium from bone, in order to maintain serum calcium within normal levels.
Obviously, the grade and duration of the vitamin D insufficiency are important. In the past, the lower limit for 25-OH vitamin D was considered
Bone metabolism during aging
Compared to the considerable amount of knowledge regarding bone metabolism, calcium exchange and vitamin D metabolism in adults and children, little is known regarding the situation in extreme longevity. It has been demonstrated that aging is accompanied by low dietary calcium intake, due to reduced intestinal absorption, altered renal re-absorption, and increment of both bone remodelling and intracellular calcium. Vitamin D levels tend to decrease, and circulating PTH levels are increased. All
Bone metabolism in centenarians
Some of the peculiarities of aging regarding calcium metabolism and vitamin D status have been confirmed in extreme senescence.
To this aim, we studied 104 subjects (90 females and 14 males) ranging between 98 and 105 years of age. They were residents in the areas of Parma and Mantova (Italy, 44° parallel north), and were living either at home or in nursing facilities. A detailed history, and general physical examinations were performed, in order to document whether any acute disease was
References (88)
Aging bone and cartilage: cross-cutting issues
Biochem. Biophys. Res. Commun.
(2005)- et al.
Estrogen (E2) regulate expression and response of 1,25-dihydroxyvitamin D3 in bone cells: changing with aging and hormone deprivation
Biochem. Biophys. Res. Commun.
(2002) A comparative radilogical study of calcified atheromas in males and females over 50 years of age
Lancet
(1957)- et al.
Shortage of circulating naive CD8 T cells provides new insights on immunodeficiency in aging
Blood
(2000) - et al.
Mini-mental state: a practical method for grading the cognitive state of patients for the clinician
J. Psychiat. Res.
(1975) - et al.
The immunology of exceptional individual: the lesson of centenarians
Immunol. Today
(1995) Functional indices of vitamin D status and ramifications of vitamin D deficiency
Am. J. Clin. Nutr.
(2004)McCollum award lecture. Vitamin D: new horizons for the 21st century
Am. J. Clin. Nutr.
(1994)- et al.
Osteoprotegerin (OPG) is a cytokine that regulates osteoclast differentiation and activation
Cell
(1998) - et al.
Thyroid and other organ-specific autoantibodies in healthy centenarians
Lancet
(1992)
Calcium, vitamin D and nutrition in the elderly
Clin. Geriatr. Med.
Osteoporosis
Lancet
Lymphocyte subsets and natural killer cell activity in healthy old-people and centenarians
Blood
Comparison of quantitative ultrasound of the phalanges with conventional bone densitometry in healthy postmenopausal women
Osteoporos. Int.
Hypovitaminosis D in older adults
Gerontology
Lipoprotein(a) and lipoprotein profile in healthy centenarians: a reappraisal of vascular risk factors
FASEB J.
Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women
Arch. Intern. Med.
Longitudinal evaluation of a bone resorption marker in elderly subjects
Osteoporos. Int.
Age-related endocrine deficiencies and fractures of the proximal femur. Implications of vitamin D deficiency in the elderly
J. Endocrinol.
Addressing the musculoskeletal component of fracture risk with calcium and vitamin D: a review of the evident
Calcif. Tissue Int.
Calcium and phosphate distribution, turnover and metabolic actions
Calcium and vitamin D in osteoporosis: supplementation or treatment?
Calcif. Tissue Int.
Vitamin D3 and calcium to prevent hip fracture in elderly women
N. Engl. J. Med.
Prevalent of vitamin D insufficiency in an adult normal population
Osteoporos Int.
Age-related-changes in parathyroid-hormone and 25 hydroxicholecalciferol levels
J. Gerontol.
Modulation of intestinal vitamin D receptor by ovariectomy, estrogen and growth hormone
Mech. Ageing Dev.
Serun vitamin D2 and vitamin D3 metabolite concentrations and absorption of vitamin D2 in elderly subjects
J. Clin. Endocrinol. Metab.
Hip fractures in the elderly: a worldwide projection
Osteoporos. Int.
DNA multiallelic systems reveal gene/longevity associations not detected by diallelic systems. The APOB locus
Hum. Genet.
AKEntAnnos. The Sardinia study of extreme longevity
Aging (Milano)
Bone formation rate in older normal women: concurrent assessment with bone histomorphometry, calcium kinetics and biological markers
J. Clin. Endocr. Metab.
Interrelationship among vitamin D metabolism, true calcium absorption, parathyroid function, and age in women: evidence of an age-related intestinal resistance to 1,25-dihydroxyvitamin D action
J. Bone Miner. Res.
Evidence of an age-related decrease in intestinal responsiveness to vitamin D: relationship between serum 1,25.dihydroxyvitamin D and intestinal vitamin D receptor concentration in normal women
J. Clin. Endocrinol. Metab.
Hip and calcaneal bone loss increase with advancing age: longitudinal results from the study of osteoporotic fractures
J. Bone Miner. Res.
Effect of age on circulating immunoreactive and bioactive parathyroid hormone levels in women
J. Bone Miner. Res.
Aging and calcium
Mineral Electrolyte Metab.
Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study
J. Bone Miner. Res.
Estrogen preserves a normal intestinal responsiveness to 1,25(OH)2D3 in oophorectomized women
J. Clin. Endocrinol. Metab.
Commonly recommended daily intake of Vitamin D is not sufficient if sunlight exposure is limited
J. Intern. Med.
Quantitative ultrasound techniques for the assessment of osteoporosis: Expert agreement on current status
J. Bone Miner. Res.
A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission
J. Gerontol. Med. Sci.
The nuclear vitamin D receptor: Biological and molecular regulatory properties revealed
J. Bone Miner. Res.
Calcium absorption varies within the reference range for serum 25-hydroxivitamin D
J. Am. Coll. Nutr.
Cited by (32)
Severe chronic hypocalcaemia in an asymptomatic patient
2017, Revista Espanola de Geriatria y GerontologiaHealthy centenarians show high levels of circulating interleukin-22 (IL-22)
2012, Archives of Gerontology and GeriatricsCitation Excerpt :Calcium levels were normal (8.86 mg/dl, normal range 8.20–10.4 mg/dl). These results are in agreement with data from the literature, in fact in centenarians deficiency of vitamin D, that has multi-factorial origin, is responsible of the secondary hyperparathyroidism, that was not due to chronic renal insufficiency (Passeri et al., 2008). Serum values of ferritin, transferrin and erythropoietin were in normal range.
Vitamin D deficiency. Not only in the elderly
2011, SemergenInvolvement of PRIP, phospholipase C-related, but catalytically inactive protein, in bone formation
2011, Journal of Biological ChemistryCitation Excerpt :In contrast to this assumption, however, female KO mice at the ages of 1, 2, 4, and 6 months exhibited increased bone mass, while those at 12 months showed a slight increase, albeit with no statistical significance. Senescence leads to slower bone turnover, probably caused by systemic down-regulation, including the reduction of osteogenic potential in bone marrow and vitamin D metabolism (42), which would be a possible explanation for the no statistical difference observed in mice at 12 months old. On the other hand, male mice at the ages of 1 and 3 months, but not of 2 weeks, showed little difference in bone mineral density as assessed by pQCT or μCT; this observation could be explained by the notion that testosterone promotes bone formation, probably hiding the impact of PRIP deficiency.
Vitamin D and aging: Beyond calcium and bone metabolism
2011, MaturitasCitation Excerpt :Raised serum levels of parathyroid hormone (PTH) produce phosphaturia and hypophosphatemia, which induce defective osteoid mineralization (osteomalacia). Low serum vitamin D levels are also associated with osteoporosis and fracture risk [7,12]. Low vitamin D levels may also be involved in other age-related diseases, including infections, cancer and cardiovascular, autoimmune and neurodegenerative diseases.
Gastroresistant microparticles containing sodium alendronate prevent the bone loss in ovariectomized rats
2010, European Journal of Pharmaceutical Sciences
- 1
For IMUSCE see Appendix 1.