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Frailty

Senile frailty is a special state of decrepitude of the body caused by aging, which is usually associated with the loss of the body's physiological reserve and a lower tolerance for stressful events. The most common definition requires the presence of 3 or more of the 5 indicators - weight loss, emaciation, weakness, sluggishness, and physical inactivity.[1] Frailty is a risk factor for many health outcomes, including falls, disability, long-term care needs, and death.[2][3] [4]

Frailty increases dramatically with age, with a prevalence of 5.2% in men and 9.6% in women over the age of 65.[5]. These rates rise to 40% in adults aged 80 and over. Frailty increases the risk of falls, delirium, disability, and other geriatric syndromes. It also increases vulnerability of age-related diseases such as neurodegeneration, myocardial infarction, stroke, type-2 diabetes, hypertension and susceptibility to viral or bacterial disease due to immune system decline.[6][7] However, some very old people (> 90 years) do not have comorbidities, which probably explains why they live longer than average. However, at some point, they "suddenly" become "brittle", and it is not yet clear why.[8] It is interesting to note that the offspring of centenarians seem to inherit the ability to resist senile infirmity - they are less prone to decrepitude than the offspring of non-centenarians.[9] Obviously, centenarians, due to the inherited genome, are better able to cope with the increasing energy costs with aging to maintain health. So, for example, many centenarians are carriers of the longevity-associated variant of the BPIFB4 gene, as a result of which they have a reduced number of immune cells with CD38 destroying NAD+ protein on the outer membrane and, as a result, have a significantly higher level of NAD+ circulating in the blood, which contributes to longevity.[10]

Criteria of frailty

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Early detection of frailty can help predict loss of mobility, the ability to go outdoors and timely take medical measures to reduce mortality among the elderly.[11][12]

The most commonly used criteria

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1. Weakness: a.) Patient reports "some difficulty", "major difficulty" or "unable to do" when asked about difficulty lifting or carrying anything up to 5 kg; b.) grip strength assessed in the dominant hand using dynamometer, where "weak" is defined as the lowest 20% of the original population adjusted for body mass index. Usually the norm is 34 ± 5 kg for men and 22 ± 5 kg for women.

2. Poor stamina: a.) The patient reports "some difficulty" or "major difficulty" when asked about difficulty moving from one room to another. b.) The patient reports any of the following in the last month: low energy, unusual tiredness, or unusual weakness.

3. Slowness: a.) slowest 20% based on the time needed to complete a 4-6 meter walk, adjusted for floor and standing height. b.) on the "up-and-go" test (get up and go) if it exceeds 12 seconds.[13]

4. Low physical activity: 'less active' response to the question 'compared to most men or women your age, would you say you are more active, less active, or about the same'.

5. Weight loss: unintentional weight loss of at least 10% after age 60 or BMI less than 18.5 kg/m2.

6. Static balance test. The ability to maintain balance affects the risk of falls and other adverse health effects. The inability to stand unsupported on one leg for 10 seconds was associated with an 84% increased risk of death from any cause over the next decade. According to the authors of the test, the proportion of those who cannot stand on one leg for 10 seconds was: about:

  • 5% among 51-55 year olds;
  • 8% among 56-60 year olds;
  • 17% among 61-65 year olds; and
  • 36% among 66-70 year olds;
  • 53% of people aged 71-75[14].

Another criterion used is the presence of the smurf phenotype (smurfness) - the pre-death period of life, when the intestinal mucosa ceases to function properly and as a result of a sharp increase in intestinal permeability ("leaky gut syndrome"), there is an increase in the translocation of microbial products such as lipopolysaccharides from the gut into the bloodstream, which subsequently causes chronic, subacute systemic inflammation not associated with infection, called inflammaging.[15][16] This criterion is more commonly used to detect frailty in small creatures such as flies. The smurf phenotype in flies is identified by blue coloring of the body after being fed a non-toxic blue food coloring, which in young flies does not normally enter the bloodstream from the gastrointestinal tract.[17] Thus, frailty is a system-level measure that can also be applied to animals.[18][19][20]

miRNA panels as potential frailty biomarkers

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Whole blood RNA-seq analysis allowed for the identification of 2 miRNAs differentially expressed in frail subjects compared to robust ones: miR-101-3p and miR-142-5p, appear to be robustly down-regulated in frail subjects.[21][22] Serum miR-451a in frail compared to robust subjects was find significantly increased and so also should be investigated as a potential biomarker for frailty.[23]

Comprehensive Geriatric Assessment (CGA)

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Frailty in elderly individuals is generally identified using comprehensive geriatric assessments (CGA), which is a multidisciplinary diagnostic process to evaluate medical, functional, psychological and social capabilities.[24] The CGA is based on evaluation of the health of older adults, exploring on 10 indicators (number of comorbidities, disability, mobility, balance, bowel/bladder function, nutrition, cognition, motivation, communication and social ability).[25][26]

The Frailty Index based on a Comprehensive Geriatric Assessment (FI-CGA) is based on the CGA, evaluates the 10 dimensions and classifies patients into three classes of frailty: mild (0–7), moderate (7–13) and severe (>13)[27]

It is interesting to note that centenarians, as persons with an extraordinary adaptive capacity, benefit from exceptional biological reserves that might be underestimated by clinical appearances and may live with debilitating disease, but still present an advantage in terms of incident disability and death. Apparently, this is why their biological FI is significantly lower than the clinical FI[28]

Transitions in frailty phenotype states

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Frailty is a dynamic process and is potentially reversible if detected early.[29][30][31] [32]

Among the factors associated with frailty of old adults, younger age, never smoking, no history of diabetes, stroke, and COPD, respectively, predicted significantly higher chances of improving frailty status. Such findings are expected, since the cause-and-effect relationships of aging mechanisms have not yet been finally determined.[33]

Chronic muscle loss increases the risk of serious falls … and even death. However, it could be detected by simple urine test "Myomar" (similar to a home-pregnancy test) designed for at-home monitoring of muscle loss.[34]

Prevention and treatment of frailty

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The best means of preventing senile infirmity is moderate physical activity and a healthy diet, as well as training memory and the ability for cognition and learning.[35]

Since an increased risk of fractures and falls leading to loss of mobility and increased hospitalizations is associated with a weakening of skeletal muscle and a decrease in their mass, the dietary supplement β-hydroxy β-methylbutyrate (beta-hydroxy-beta-methylbutyrate, HMB) with anabolic and anti-catabolic properties has been proposed for long-term use, as one of the means of preventing senile frailty in people over 65 years, particularly in bedridden or sedentary.[36] Daily intake of 2-3 grams of this drug improves muscle quality and does not have pronounced side effects.[37][38][39][40][41] In older adults with sarcopenia, HMB significantly enhance the effect of resistance exercise training on muscle strength, physical performance, muscle quality, and reduced inflammatory factors.[42] According to preclinical studies in rodents, HMB may also improve learning and working memory.[43][44] Since calcium β-hydroxy-β-methylbutyrate is less well absorbed by the body, it is advisable to use dietary supplements or high-protein foods to which β-hydroxy-β-methylbutyrate has been added, while calcium supplements to be given separately.[45]

Cholecalciferol (vitamin D3) deficiency has been identified as a risk factor for accelerated muscle loss, poor physical performance and falls.[46] Therefore, it is recommended that those patients with vitamin D3 levels below 30 ng/ml also take for three months vitamin D3 capsules (1000-2000 IU/day divided into two doses) or until its serum level reaches a sufficient range (30-60 ng/ml).[47]

Fall risks and how to reduce the likelihood of fall-induced injury

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Having a poorly set up home comes with a whole plethora of fall risks. Most of them are fairly easy to modify to promote safety prevention.[48] These include:

  • Stairs. Poor endurance and strength for navigating them, lack of handrails, or poor stair design.
  • Entrances. Having a lip or elevated sill in the door frame, having stairs, or lack of handrails.
  • Bathroom. Lack of grab bars, low toilet seat, or a high rise tub.
  • Slippery or uneven surfaces. Including wet floors, ice, and walking on moveable surfaces such as carpet, grass or gravel.
  • Clutter and tripping hazards. This includes doormats and area rugs that a foot can easily catch on in addition to general disorganization.
  • Poor lighting throughout the home. Particularly from the bedroom to the bathroom in the middle of the night.
  • Medications. Ones that affect cognition, coordination, and vision such as psychoactives, opiates, anticonvulsants, diuretics, laxatives, and sedatives.
  • Improper use of assistive devices. Having a grab bar, cane or walker can become hazardous if not used precisely and in a coordinated manner.


Technologies designed to reduce the likelihood of fall-induced injury:

  • Compliant flooring as a passive intervention approach designed to reduce the stiffness of the ground in order to attenuate the impact forces applied to the body in the event of a fall.
  • The raised, warm, soft, toilet seat with adjustebl height and weight-bearing armrests allows for extended sitting without discomfort and that can be used as a raised toilet seat/bedside commode/shower chair.[49]

References

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  1. ↑ Clegg, A., Young, J., Iliffe, S., Rikkert, M. O., & Rockwood, K. (2013). Frailty in elderly people. The lancet, 381(9868), 752-762. PMID:23395245 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098658 DOI:https://doi.org/10.1016/S0140-6736(12)62167-9
  2. ↑ Csete, M. E. (2021). Basic Science of Frailty—Biological Mechanisms of Age-Related Sarcopenia. Anesthesia & Analgesia, 132(2), 293-304. PMID:32769382 DOI:https://doi.org/10.1213/ANE.0000000000005096
  3. ↑ Li, X., Schöttker, B., Holleczek, B., & Brenner, H. (2022). Association of longitudinal repeated measurements of frailty index with mortality: Cohort study among community-dwelling older adults. EClinicalMedicine, 53, 101630. PMID:36119560 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9475257 DOI:https://doi.org/10.1016/j.eclinm.2022.101630
  4. ↑ Watanabe, D., Yoshida, T., Yamada, Y., Watanabe, Y., Yamada, M., Fujita, H., ... & Kimura, M. (2022). Combined use of two frailty tools in predicting mortality in older adults. Scientific reports, 12(1), 1-9. PMID: 36057638 PMC9440890 DOI: https://doi.org/10.1038/s41598-022-19148-x
  5. ↑ Collard R.M., Boter H., Schoevers R.A., Oude Voshaar R.C. Prevalence of Frailty in Community-Dwelling Older Persons: A Systematic Review. J. Am. Geriatr. Soc. 2012;60:1487–1492. doi:https://doi.org/10.1111/j.1532-5415.2012.04054.x.
  6. ↑ Cuenca, S. L., López, L. O., Martín, N. L., Jaimes, M. I., Villamayor, M. I., Artigas, A., & Balanza, J. L. (2019). Frailty in patients over 65 years of age admitted to Intensive Care Units (FRAIL-ICU). Medicina Intensiva (English Edition), 43(7), 395-401. PMID:30905473 DOI:https://doi.org/10.1016/j.medin.2019.01.010
  7. ↑ Ribeiro, A. R., Howlett, S. E., & Fernandes, A. (2020). Frailty—A promising concept to evaluate disease vulnerability. Mechanisms of ageing and development, 187, 111217. PMID:32088282 DOI:https://doi.org/10.1016/j.mad.2020.111217
  8. ↑ Takeda, C., Angioni, D., Setphan, E., Macaron, T., Barreto, P. D. S., Sourdet, S., ... & Vellas, B. (2020). Age-Related Frailty: A Clinical Model for Geroscience?. The journal of nutrition, health & aging, 24(10), 1140-1143. PMID:33244574 DOI:https://doi.org/10.1007/s12603-020-1491-4
  9. ↑ Inglés, M., Belenguer-Varea, A., Serna, E., Mas-Bargues, C., Tarazona-Santabalbina, F. J., Borrás, C., & Vina, J. (2022). Functional transcriptomic analysis of centenarians’ offspring reveals a specific genetic footprint that may explain that they are less frail than age-matched non-centenarians’ offspring. The Journals of Gerontology: Series A. 77(10), 1931-1938 PMID:35640160 DOI:https://doi.org/10.1093/gerona/glac119
  10. ↑ Ciaglia, E., Lopardo, V., Montella, F., Carrizzo, A., Di Pietro, P., Malavolta, M., ... & Puca, A. A. (2022). Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline. Cell death & disease, 13(1), 1-10. PMID:35087020 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8792139 DOI:https://doi.org/10.1038/s41419-022-04535-z
  11. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Anabitarte
  12. ↑ Sepúlveda, M., Arauna, D., García, F., Albala, C., Palomo, I., & Fuentes, E. (2022). Frailty in Aging and the Search for the Optimal Biomarker: A Review. Biomedicines, 10(6), 1426. PMID: 35740447 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9219911 DOI: https://doi.org/10.3390/biomedicines10061426
  13. ↑ Zhou, J., Liu, B., Qin, M. Z., & Liu, J. P. (2021). A prospective cohort study of the risk factors for new falls and fragility fractures in self-caring elderly patients aged 80 years and over. BMC geriatrics, 21(1), 1-9. PMID|33568077 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877083 DOI:https://doi.org/10.1186/s12877-021-02043-x
  14. ↑ Gil Araujo C. et al. (2022). Successful 10-second one-legged stance performance predicts survival in middle-aged and older individuals. British Journal of Sports Medicine doi:https://doi.org/10.1136/bjsports-2021-105360
  15. ↑ Kavanagh, K., Hsu, F. C., Davis, A. T., Kritchevsky, S. B., Rejeski, W. J., & Kim, S. (2019). Biomarkers of leaky gut are related to inflammation and reduced physical function in older adults with cardiometabolic disease and mobility limitations. Geroscience, 41(6), 923-933. PMID|31654268 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925090 doi:https://doi.org/10.1007/s11357-019-00112-z
  16. ↑ Dambroise, E., Monnier, L., Ruisheng, L. , Aguilaniu, H., Joly, J. S., Tricoire, H., & Rera, M. (2016). Two phases of aging separated by the Smurf transition as a public path to death. Scientific reports, 6(1), 1-7. PMID|27002861 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802314 doi:https://doi.org/10.1038/srep23523
  17. ↑ Martins, R. R., McCracken, A. W., Simons, M. J., Henriques, C. M. , & Rera, M. (2018). How to catch a smurf?–Ageing and beyond… In vivo assessment of intestinal permeability in multiple model organisms. Bio-protocol, 8(3), e2722-e2722. PMID|29457041 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812435 DOI:https://doi.org/10.21769/BioProtoc.2722
  18. ↑ Howlett, S. E., Rutenberg, A. D., & Rockwood, K. (2021). The degree of frailty as a translational measure of health in aging. Nature Aging, 1(8), 651-665. https://doi.org/10.1038/s43587-021-00099-3
  19. ↑ Schultz, M. B., Kane, A. E., Mitchell, S. J., MacArthur, M. R., Warner, E., Vogel, D. S., ... & Sinclair, D. A. (2020). Age and life expectancy clocks based on machine learning analysis of mouse frailty. Nature communications, 11(1), 1-12.
  20. ↑ Liu, P., Li, Y., & Ma, L. (2022). Frailty in rodents: models, underlying mechanisms, and management. Ageing Research Reviews, 101659. https://doi.org/10.1016/j.arr.2022.101659
  21. ↑ Carini, G., Mingardi, J., Bolzetta, F., Cester, A., Bolner, A., Nordera, G., ... & Barbon, A. (2022). miRNome profiling detects miR-101-3p and miR-142-5p as putative blood biomarkers of frailty syndrome. Genes, 13(2), 231. PMID: 35205276 PMCID: PMC8872439 DOI: 10.3390/genes13020231
  22. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Dato
  23. ↑ Agostini, S., Mancuso, R., Citterio, L. A., Mihali, G. A., Arosio, B., & Clerici, M. (2023). Evaluation of serum miRNAs expression in frail and robust subjects undergoing multicomponent exercise protocol (VIVIFRAIL). Journal of Translational Medicine, 21(1), 67. PMID: 36726153 PMCID: PMC9891895 DOI: 10.1186/s12967-023-03911-3
  24. ↑ Fox, S. T., Janda, M., & Hubbard, R. (2022). Understanding how comprehensive geriatric assessment works: the importance of varied methodological approaches. Aging Clinical and Experimental Research, 1-7. PMID: 36451033 DOI: https://doi.org/10.1007/s40520-022-02305-7
  25. ↑ Lee, H., Lee, E., & Jang, I. Y. (2020). Frailty and comprehensive geriatric assessment. Journal of Korean medical science, 35(3). PMID: 31950775 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970074 DOI: https://doi.org/10.3346/jkms.2020.35.e16
  26. ↑ Turner, G., & Clegg, A. (2014). Best practice guidelines for the management of frailty: a British Geriatrics Society, Age UK and Royal College of General Practitioners report. Age and ageing, 43(6), 744-747. https://doi.org/10.1093/ageing/afu138
  27. ↑ Ilie, A. C., Taranu, S. M., Stefaniu, R., Sandu, I. A., Pislaru, A. I., Sandu, C. A., ... & Alexa, I. D. (2022). Chronic Coronary Syndrome in Frail Old Population. Life, 12(8), 1133. https://doi.org/10.3390/life12081133
  28. ↑ Arosio, B., Geraci, A., Ferri, E., Mari, D., & Cesari, M. (2022). Biological Frailty Index in centenarians. Aging clinical and experimental research, 34(3), 687-690. DOI: https://doi.org/10.1007/s40520-021-01993-x
  29. ↑ Qualls, C., Waters, D. L., Vellas, B., Villareal, D. T., Garry, P. J., Gallini, A., & Andrieu, S. (2017). Reversible states of physical and/or cognitive dysfunction: a 9-year longitudinal study. The journal of nutrition, health & aging, 21(3), 271-275. DOI: https://doi.org/10.1007/s12603-017-0878-3
  30. ↑ Negm, A. M., Kennedy, C. C., Thabane, L., Veroniki, A. A., Adachi, J. D., Richardson, J., ... & Papaioannou, A. (2019). Management of frailty: a systematic review and network meta-analysis of randomized controlled trials. Journal of the American Medical Directors Association, 20(10), 1190-1198.
  31. ↑ Gagesch, M., Wieczorek, M., Vellas, B. et al. (2022). Effects of Vitamin D, Omega-3 Fatty Acids and a Home Exercise Program on Prevention of Pre-Frailty in Older Adults: The DO-HEALTH Randomized Clinical Trial. J Frailty Aging, DOI: https://doi.org/10.14283/jfa.2022.48
  32. ↑ Kojima, G., Taniguchi, Y., Iliffe, S., Jivraj, S., & Walters, K. (2019). Transitions between frailty states among community-dwelling older people: a systematic review and meta-analysis. Ageing research reviews, 50, 81-88. https://doi.org/10.1016/j.arr.2019.01.010
  33. ↑ Kojima, G., Taniguchi, Y., Iliffe, S., Urano, T., & Walters, K. (2019). Factors associated with improvement in frailty status defined using the frailty phenotype: a systematic review and meta-analysis. Journal of the American Medical Directors Association, 20(12), 1647-1649. https://doi.org/10.1016/j.jamda.2019.05.018
  34. ↑ Myomar Molecular Inc. admmyomar@myomarmolecular.com 1344 Summer St Halifax, NS B3H4R2 Dalhousie University
  35. ↑ Teh, R., Barnett, D., Edlin, R., Kerse, N., Waters, D. L., Hale, L., ... & Pillai, A. (2022). Effectiveness of a complex intervention of group-based nutrition and physical activity to prevent frailty in pre-frail older adults (SUPER): a randomised controlled trial. The Lancet Healthy Longevity, 3(8), e519-e530. PMID: 36102762 DOI: https://doi.org/10.1016/S2666-7568(22)00124-6
  36. ↑ Rathmacher, J. A., Pitchford, L. M., Khoo, P., Angus, H. , Lang, J., Lowry, K., ... & Sharp, R. L. (2020). Long-term Effects of Calcium β-Hydroxy-β-Methylbutyrate and Vitamin D3 Supplementation on Muscular Function in Older Adults With and Without Resistance Training: A Randomized, Double-blind, Controlled Study. The Journals of Gerontology: Series A, 75(11), 2089-2097. PMID:32857128 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566440 DOI: https://doi.org/10.1093/gerona/glaa218
  37. ↑ Oktaviana, J., Zanker, J., Vogrin, S., & Duque, G. (2019). The effect of β-hydroxy-β-methylbutyrate (HMB) on sarcopenia and functional frailty in older persons: a systematic review. The journal of nutrition, health & aging, 23(2), 145-150. PMID:30697623 DOI: https://doi.org/10.1007/s12603-018-1153-y
  38. ↑ Costa Riela NA, Alvim Guimarães MM, Oliveira de Almeida D, Araujo EMQ. (2021). Effects of Beta-Hydroxy-Beta-Methylbutyrate Supplementation on Elderly Body Composition and Muscle Strength: A Review of Clinical Trials Ann Nutr Metab.
  39. ↑ Marshall, R. N., Smeuninx, B., Morgan, P. T., & Breen, L. (2020). Nutritional strategies to offset disuse-induced skeletal muscle atrophy and anabolic resistance in older adults: From whole-foods to isolated ingredients. Nutrients, 12(5), 1533. PMID:32466126 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284346 DOI: https://doi.org/10.3390/nu12051533
  40. ↑ Davinelli, S., Corbi , G., & Scapagnini, G. (2021). Frailty syndrome: A target for functional nutrients?. Mechanisms of Aging and Development, 111441. PMID:33539905 DOI: https://doi.org/10.1016/j.mad.2021.111441
  41. ↑ Tamura, Y., Omura, T., Toyoshima, K., & Araki, A. (2020). Nutrition Management in Older Adults with Diabetes: A Review on the Importance of Shifting Prevention Strategies from Metabolic Syndrome to Frailty. Nutrients, 12(11), 3367. PMID:33139628 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693664 DOI: https://doi.org/10.3390/nu12113367
  42. ↑ Yang, C., Song, Y., Li, T., Chen, X., Zhou, J., Pan, Q., ... & Jia, H. (2023). Effects of Beta-Hydroxy-Beta-Methylbutyrate Supplementation on Older Adults with Sarcopenia: A Randomized, Double-Blind, Placebo-Controlled Study. The journal of nutrition, health & aging, 1-11. https://doi.org/10.1007/s12603-023-1911-1
  43. ↑ Munroe, M., Mahmassani, Z. S., Dvoretskiy, S., Reid, J. J., Miller, B. F., Hamilton, K., ... & Boppart, M. D. (2020). Cognitive function is preserved in aged mice following long-term β-hydroxy β-methylbutyrate supplementation. Nutritional Neuroscience, 23(3), 170-182. PMID: 29914347 DOI: 10.1080/1028415X.2018.1483101
  44. ↑ Barranco Pérez, A., García, L., Rueda, R., & Ramírez, M. (2022). Effects of beta-Hydroxy beta-Methylbutyrate Supplementation on Working Memory and Hippocampal Long-Term Potentiation in Rodents. Nutrients, 14(5):1090. PMID: 35268065 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912805 DOI: 10.3390/nu14051090
  45. ↑ Peng, LN., Cheng, YC., Yu, PC. et al. (2021). Oral Nutritional Supplement with β-hydroxy-β-methylbutyrate (HMB) Improves Nutrition, Physical Performance and Ameliorates Intramuscular Adiposity in Pre-Frail Older Adults: A Randomized Controlled Trial. J Nutr Health Aging doi: https://doi.org/10.1007/s12603-021-1621-7
  46. ↑ Wintermeyer, E., Ihle, C., Ehnert, S., Stöckle, U., Ochs, G., De Zwart, P., ... & Nussler, A. K. (2016). Crucial role of vitamin D in the musculoskeletal system. Nutrients, 8(6), 319. PMID:27258303 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924160 DOI: https://doi.org/10.3390/nu8060319
  47. ↑ Rathmacher, J. A., Pitchford, L. M., Khoo, P., Angus, H., Lang, J., Lowry, K., ... & Sharp, R. L. (2020). Long-term Effects of Calcium β-Hydroxy-β-Methylbutyrate and Vitamin D3 Supplementation on Muscular Function in Older Adults With and Without Resistance Training: A Randomized, Double-blind, Controlled Study. The Journals of Gerontology: Series A, 75(11), 2089-2097. PMID:32857128 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566440 doi: https://doi.org/10.1093/gerona/glaa218
  48. ↑ JayDee (2923). Fall Prevention At Home In The Elderly: Common Causes, Risk Factors and How To Prevent Them. Senior Homecare HQ
  49. ↑ The Ultimate Raised Toilet Seat, Voted 1 Most Comfortable
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