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The variation in the life-course trajectory of frailty and how it influences the clinical practice of end-of-life care

      Life begins as embryos with similar phenotypes but different genotypes. With maturation, body function peaks at youth, and starts to decline throughout mid-life and late life. With different genetic and environmental influences, the variation among individuals in body function decline widens [
      • Lowsky D.J.
      • Olshansky S.J.
      • Bhattacharya J.
      • Goldman D.P.
      Heterogeneity in healthy aging.
      ,
      • Mitnitski A.
      • Howlett S.E.
      • Rockwood K.
      Heterogeneity of human aging and its assessment.
      ,
      • Ylikoski R.
      • Ylikoski A.
      • Keskivaara P.
      • Tilvis R.
      • Sulkava R.
      • Erkinjuntti T.
      Heterogeneity of cognitive profiles in aging: successful aging, normal aging, and individuals at risks for cognitive decline.
      ,
      • Ardila A.
      Normal aging increases cognitive heterogeneity: analysis of dispersion in WAIS-III scores across age.
      ], although we are phenotypically similar at conception. In old age, frailty comes in and the trajectory similarly will vary widely in the older population. However, this variation may not continue to widen but, instead, in the terminal stage of life the variation can diminish. Moreover, this phenomenon is often not well noticed by clinicians. The complete life-course trajectory of the development and decline of two individuals, which begins with increasing variation and ends with convergence at the end stage of life, is illustrated conceptually in the Fig. 1 [
      • Auyeung T.W.
      • Lee S.W.
      Life-course trajectory of frailty and its clinical applications: a narrative review.
      ]. The Frailty Index (FI) [
      • Rockwood K.
      • Song X.
      • MacKnight C.
      • Bergman H.
      • Hogan D.B.
      • McDowell I.
      • et al.
      A global clinical measure of fitness and frailty in elderly people.
      ], represented by the extent of deficits accumulation, can shed light on how this variation behaves at the final stage of life. Mitnitski et al. measured the FI of a group of patients with early-stage Alzheimer's disease (AD). The diversity of FIs in the group was wide. However, with advancement of the disease and accumulation of multiple deficits on top of the neurodegenerative disorder, the variability among the group diminished. [
      • Mitnitski A.B.
      • Mogilner A.J.
      • Rockwood K.
      Accumulation of deficits as a proxy measure of aging.
      ] The coefficient of variation within a group of patients with a certain stage of the disease diminished from 0.612 (N = 921) in persons with no cognitive impairment to 0.279 (N = 72) in persons with severe dementia. [
      • Mitnitski A.B.
      • Mogilner A.J.
      • Rockwood K.
      Accumulation of deficits as a proxy measure of aging.
      ] Most of the persons at the late stage of AD will have a FI converged at around 0.4. [
      • Mitnitski A.B.
      • Mogilner A.J.
      • Rockwood K.
      Accumulation of deficits as a proxy measure of aging.
      ] In addition, Nguyen et al. in the Canadian Longitudinal Study which followed 30,097 adults aged 45 to 86years demonstrated that the heterogeneity of aging did not widen continuously but rather peaked at the age of 70 years and became less heterogeneous in the older age groups. [
      • Nguyen Q.D.
      • Moodie E.M.
      • Forget M.F.
      • Desmarais P.
      • Keezer M.R.
      • Wolfson C.
      Health heterogeneity in older adults: exploration in the Canadian longitudinal study on aging.
      ] However, Ferrucci et al. in the editorial of the same issue have commented that this observation can be biased by the ‘healthy survivor’ effect in the more advanced age groups. [
      • Ferrucci L.
      • Kuchel G.A.
      Heterogeneity of aging: individual risk factors, mechanisms, patient priorities, and outcomes.
      ] Therefore it is still controversial whether the heterogeneity of aging is less in advanced old age. However, if it is true a complete life-course trajectory of frailty should, therefore, follow the configuration as described in the lower panel of the Fig. 1. Perhaps the variability in the life-course trajectory of body function and frailty will vary from homogeneity at the embryo stage, to heterogeneity at late-life stage, and reverting back to homogeneity at the end-of-life stage (Fig. 1). [
      • Auyeung T.W.
      • Lee S.W.
      Life-course trajectory of frailty and its clinical applications: a narrative review.
      ]
      Fig. 1
      Fig. 1Life course trajectory of frailty.
      (Adapted from Auyeung TW et al. [
      • Auyeung T.W.
      • Lee S.W.
      Life-course trajectory of frailty and its clinical applications: a narrative review.
      ]).

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