Introduction: Immunosenescence and inflammaging have been implicated in the pathophysiology of frailty. Torquetenovirus (TTV), a single-stranded DNA anellovirus, the major component of the human blood virome, shows an increased replication rate with advancing age. An elevated TTV viremia has been associated with an impaired immune function and an increased risk of mortality in the older population. The objective of this study was to analyze the relation between TTV viremia, physical frailty, and cognitive impairment. Methods: TTV viremia was measured in 1,131 nonfrail, 45 physically frail, and 113 cognitively impaired older adults recruited in the MARK-AGE study (overall mean age 64.7 ± 5.9 years), and then the results were checked in two other independent cohorts from Spain and Portugal, including 126 frail, 252 prefrail, and 141 nonfrail individuals (overall mean age: 77.5 ± 8.3 years). Results: TTV viremia ≥4log was associated with physical frailty (OR: 4.69; 95% CI: 2.06–10.67, p < 0.0001) and cognitive impairment (OR: 3.49, 95% CI: 2.14–5.69, p < 0.0001) in the MARK-AGE population. The association between TTV DNA load and frailty status was confirmed in the Spanish cohort, while a slight association with cognitive impairment was observed (OR: 1.33; 95% CI: 1.000–1.773), only in the unadjusted model. No association between TTV load and frailty or cognitive impairment was found in the Portuguese sample, although a negative association between TTV viremia and MMSE score was observed in Spanish and Portuguese females. Conclusions: These findings demonstrate an association between TTV viremia and physical frailty, while the association with cognitive impairment was observed only in the younger population from the MARK-AGE study. Further research is necessary to clarify TTV’s clinical relevance in the onset and progression of frailty and cognitive decline in older individuals.

Okamoto H, Ukita M, Nishizawa T, Kishimoto J, Hoshi Y, Mizuo H, et al. Circular double-stranded forms of TT virus DNA in the liver. J Virol. 2000 Jun;74(11):5161–7.
Focosi D, Antonelli G, Pistello M, Maggi F. Torquetenovirus: the human virome from bench to bedside. Clin Microbiol Infect. 2016 Jul;22(7):589–93.
Focosi D, Spezia PG, Macera L, Salvadori S, Navarro D, Lanza M, et al. Assessment of prevalence and load of torquetenovirus viraemia in a large cohort of healthy blood donors. Clin Microbiol Infect. 2020 Oct;26(10):1406–10.
Giacconi R, Maggi F, Macera L, Spezia PG, Pistello M, Provinciali M, et al. Prevalence and loads of torquetenovirus in the European mark-age study population. J Gerontol A Biol Sci Med Sci. 2020 Oct;75(10):1838–45.
Schmitz J, Kobbe G, Kondakci M, Schuler E, Magorsch M, Adams O. The value of torque teno virus (TTV) as a marker for the degree of immunosuppression in adult patients after hematopoietic stem cell transplantation (HSCT): TTV as a biomarker in adult patients after HSCT. Biol Blood Marrow Transpl. 2020 Apr;26(4):643–50.
Giacconi R, Maggi F, Macera L, Pistello M, Provinciali M, Giannecchini S, et al. Torquetenovirus (TTV) load is associated with mortality in Italian elderly subjects. Exp Gerontol. 2018 Oct;112:103–11.
Pou C, Barrientos-Somarribas M, Marin-Juan S, Bogdanovic G, Bjerkner A, Allander T, et al. Virome definition in cerebrospinal fluid of patients with neurological complications after hematopoietic stem cell transplantation. J Clin Virol. 2018 Nov;108: 112–20.
Pifferi M, Maggi F, Andreoli E, Lanini L, Marco ED, Fornai C, et al. Associations between nasal torquetenovirus load and spirometric indices in children with asthma. J Infect Dis. 2005 Oct;192(7):1141–8.
Rocchi J, Ricci V, Albani M, Lanini L, Andreoli E, Macera L, et al. Torquetenovirus DNA drives proinflammatory cytokines production and secretion by immune cells via toll-like receptor 9. Virology. 2009 Nov;394(2):235–42.
Wang GC, Kao WHL, Murakami P, Xue QL, Chiou RB, Detrick B, et al. Cytomegalovirus infection and the risk of mortality and frailty in older women: a prospective observational cohort study. Am J Epidemiol. 2010 May;171(10):1144–52.
Ng TP, Lu Y, Tan CTY, Gao Q, Gwee X, Fulop T, et al. Pathogenic load and frailty in older adults: Singapore longitudinal ageing study. Aging. 2020 Nov;12(21):22139–51.
Strandberg TE, Pitkala KH, Linnavuori KH, Tilvis RS. Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke. 2003 Sep;34(9):2126–31.
Letenneur L, Pérès K, Fleury H, Garrigue I, Barberger-Gateau P, Helmer C, et al. Seropositivity to herpes simplex virus antibodies and risk of Alzheimer’s disease: a population-based cohort study. PLoS One. 2008 Nov;3(11):e3637.
Capri M, Moreno-Villanueva M, Cevenini E, Pini E, Scurti M, Borelli V, et al. MARK-AGE population: from the human model to new insights. Mech Ageing Dev. 2015 Nov;151:13–7.
Bürkle A, Moreno-Villanueva M, Bernhard J, Blasco M, Zondag G, Hoeijmakers JHJ, et al. MARK-AGE biomarkers of ageing. Mech Ageing Dev. 2015 Nov;151:2–12.
Moreno-Villanueva M, Capri M, Breusing N, Siepelmeyer A, Sevini F, Ghezzo A, et al. MARK-AGE standard operating procedures (SOPs): a successful effort. Mech Ageing Dev. 2015 Nov;151:18–25.
Moreno-Villanueva M, Kötter T, Sindlinger T, Baur J, Oehlke S, Bürkle A, et al. The MARK-AGE phenotypic database: structure and strategy. Mech Ageing Dev. 2015 Nov;151:26–30.
Jansen E, Beekhof P, Cremers J, Weinberger B, Fiegl S, Toussaint O, et al. Quality control data of physiological and immunological biomarkers measured in serum and plasma. Mech Ageing Dev. 2015 Nov;151:54–9.
Valdiglesias V, Sánchez-Flores M, Marcos-Perez D, Lorenzo-López L, Maseda A, Millán-Calenti JC, et al. Exploring genetic outcomes as frailty biomarkers. J Gerontol A Biol Sci Med Sci. 2019 Jan;74(2):168–75.
Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146–56.
Rietman ML, Spijkerman AMW, Wong A, van Steeg H, Bürkle A, Moreno-Villanueva M, et al. Antioxidants linked with physical, cognitive and psychological frailty: analysis of candidate biomarkers and markers derived from the MARK-AGE study. Mech Ageing Dev. 2019 Jan;177:135–43.
Sánchez-Flores M, Marcos-Pérez D, Lorenzo-López L, Maseda A, Millán-Calenti JC, Bonassi S, et al. Frailty syndrome and genomic instability in older adults: suitability of the cytome micronucleus assay as a diagnostic tool. J Gerontol A Biol Sci Med Sci. 2018 Jun;73(7):864–72.
Teixeira-Gomes A, Lage B, Esteves F, Sousa AC, Pastorinho MR, Valdiglesias V, et al. Frailty syndrome, biomarkers and environmental factors: a pilot study. Toxicol Lett. 2020 Sep;330:14–22.
Blesa R, Pujol M, Aguilar M, Santacruz P, Bertran-Serra I, Hernández G, et al. Clinical validity of the “mini-mental state” for spanish speaking communities. Neuropsychologia. 2001;39(11):1150–7.
Morgado J, Rocha CS, Maruta C, Guerreiro M, Martins IP. Cut-off scores in MMSE: a moving target? Eur J Neurol. 2010 May;17(5):692–5.
Maggi F, Andreoli E, Lanini L, Fornai C, Vatteroni M, Pistello M, et al. Relationships between total plasma load of torquetenovirus (TTV) and TTV genogroups carried. J Clin Microbiol. 2005 Sep;43(9):4807–10.
Robertson DA, Savva GM, Kenny RA. Frailty and cognitive impairment-A review of the evidence and causal mechanisms. Ageing Res Rev. 2013 Sep;12(4):840–51.
Malmstrom TK, Morley JE. Frailty and cognition: linking two common syndromes in older persons. J Nutr Health Aging. 2013 Nov;17(9):723–5.
Howlett SE, Rockwood MRH, Mitnitski A, Rockwood K. Standard laboratory tests to identify older adults at increased risk of death. BMC Med. 2014 Oct;12(1):171.
Franceschi C, Campisi J. Chronic inflammation (Inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014 Jun;69(Suppl 1):S4–9.
Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Löfgren S, et al. An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci. 2005;60(5):556–65.
Goldeck D, Adriaensen W, Oettinger L, Vaes B, Van Pottelbergh G, Degryse JM, et al. Cellular immune phenotypes and worsening scores of frailty-associated parameters over an 18-month period in the very old. J Gerontol A Biol Sci Med Sci. 2021 Aug;76(8):1356–61.
Spandole-Dinu S, Cimponeriu DG, Crăciun AM, Radu I, Nica S, Toma M, et al. Prevalence of human anelloviruses in Romanian healthy subjects and patients with common pathologies. BMC Infect Dis. 2018 Jul;18(1):334.
Springfeld C, Bugert JJ, Schnitzler P, Tobiasch E, Kehm R, Darai G. TT virus as a human pathogen: significance and problems. Virus Genes. 2000;20(1):35–45.
Haloschan M, Bettesch R, Görzer I, Weseslindtner L, Kundi M, Puchhammer-Stöckl E. TTV DNA plasma load and its association with age, gender, and HCMV IgG serostatus in healthy adults. Age. 2014 Oct;36(5):9716.
Marcos-Pérez D, Sánchez-Flores M, Proietti S, Bonassi S, Costa S, Teixeira JP, et al. Association of inflammatory mediators with frailty status in older adults: results from a systematic review and meta-analysis. GeroScience. 2020 Dec;42(6):1451–73.
Ruan Q, D’Onofrio G, Sancarlo D, Greco A, Lozupone M, Seripa D, et al. Emerging biomarkers and screening for cognitive frailty. Aging Clin Exp Res. 2017 Dec;29(6):1075–86.
Luz Correa B, Ornaghi AP, Cerutti Muller G, Engroff P, Pestana Lopes R, Gomes Da Silva Filho I, et al. The inverted CD4:CD8 ratio is associated with cytomegalovirus, poor cognitive and functional states in older adults. Neuroimmunomodulation. 2014;21(4):206–12.
Barbé-Tuana F, Funchal G, Schmitz CRR, Maurmann RM, Bauer ME. The interplay between immunosenescence and age-related diseases. Semin Immunopathol. 2020 Oct;42(5):545–57.
Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci U S A. 2004 May;101(21):8180–5.
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