Background Activities of daily living (ADLs) and instrumental activities of daily living (IADLs) are essential for independent living and are predictors of morbidity and mortality in older populations. Older adults who are dependent in ADLs and IADLs are also more likely to have poor muscle measures defined as low muscle mass, muscle strength, and physical performance, which further limit their ability to perform activities. The aim of this systematic review and meta‐analysis was to determine if muscle measures are predictive of ADL and IADL in older populations. Methods A systematic search was conducted using four databases (MEDLINE, EMBASE, Cochrane, and CINAHL) from date of inception to 7 June 2018. Longitudinal cohorts were included that reported baseline muscle measures defined by muscle mass, muscle strength, and physical performance in conjunction with prospective ADL or IADL in participants aged 65 years and older at follow‐up. Meta‐analyses were conducted using a random effect model. Results Of the 7760 articles screened, 83 articles were included for the systematic review and involved a total of 108 428 (54.8% female) participants with a follow‐up duration ranging from 11 days to 25 years. Low muscle mass was positively associated with ADL dependency in 5/9 articles and 5/5 for IADL dependency. Low muscle strength was associated with ADL dependency in 22/34 articles and IADL dependency in 8/9 articles. Low physical performance was associated with ADL dependency in 37/49 articles and with IADL dependency in 9/11 articles. Forty‐five articles were pooled into the meta‐analyses, 36 reported ADL, 11 reported IADL, and 2 reported ADL and IADL as a composite outcome. Low muscle mass was associated with worsening ADL (pooled odds ratio (95% confidence interval) 3.19 (1.29–7.92)) and worsening IADL (1.28 (1.02–1.61)). Low handgrip strength was associated with both worsening ADL and IADL (1.51 (1.34–1.70); 1.59 (1.04–2.31) respectively). Low scores on the short physical performance battery and gait speed were associated with worsening ADL (3.49 (2.47–4.92); 2.33 (1.58–3.44) respectively) and IADL (3.09 (1.06–8.98); 1.93 (1.69–2.21) respectively). Low one leg balance (2.74 (1.31–5.72)), timed up and go (3.41 (1.86–6.28)), and chair stand test time (1.90 (1.63–2.21)) were associated with worsening ADL. Conclusions Muscle measures at baseline are predictors of future ADL and IADL dependence in the older adult population.

The heterotrimeric DNA-binding protein, replication protein A (RPA), consists of 70-, 34-, and 14-kDa subunits and is involved in maintaining genomic stability by playing key roles in DNA replication, repair, and recombination. RPA participates in these processes through its interaction with other proteins and its strong affinity for single-stranded DNA (ssDNA). RPA-p34 is phosphorylated in a cell-cycle-dependent fashion primarily at Ser-29 and Ser-23, which are consensus sites for Cdc2 cyclin-dependent kinase. By systematically examining RPA-p34 phosphorylation throughout the cell cycle, we have found there are distinct phosphorylated forms of RPA-p34 in different cell-cycle stages. We have isolated and purified a unique phosphorylated form of RPA that is specifically associated with the mitotic phase of the cell cycle. The mitotic form of RPA (m-hRPA) shows no difference in ssDNA binding activity as compared with recombinant RPA (r-hRPA), yet binds less efficiently to double-stranded DNA (dsDNA). These data suggest that mitotic phosphorylation of RPA-p34 inhibits the destabilization of dsDNA by RPA complex, thereby decreasing the binding affinity for dsDNA. The m-hRPA also exhibits altered interactions with certain DNA replication and repair proteins. Using highly purified proteins, m-hRPA exhibited decreased binding to ATM, DNA pol alpha, and DNA-PK as compared to unphosphorylated recombinant RPA (r-hRPA). Dephosphorylation of m-hRPA was able to restore the interaction with each of these proteins. Interestingly, the interaction of RPA with XPA was not altered by RPA phosphorylation. These data suggest that phosphorylation of RPA-p34 plays an important role in regulating RPA functions in DNA metabolism by altering specific protein-protein interactions.

Exposure to DNA-damaging agents triggers signal transduction pathways that are thought to play a role in maintenance of genomic stability. A key protein in the cellular processes of nucleotide excision repair, DNA recombination, and DNA double-strand break repair is the single-stranded DNA binding protein, RPA. We showed previously that the p34 subunit of RPA becomes hyperphosphorylated as a delayed response (4-8 h) to UV radiation (10-30 J/m(2)). Here we show that UV-induced RPA-p34 hyperphosphorylation depends on expression of ATM, the product of the gene mutated in the human genetic disorder ataxia telangiectasia (A-T). UV-induced RPA-p34 hyperphosphorylation was not observed in A-T cells, but this response was restored by ATM expression. Furthermore, purified ATM kinase phosphorylates the p34 subunit of RPA complex in vitro at many of the same sites that are phosphorylated in vivo after UV radiation. Induction of this DNA damage response was also dependent on DNA replication; inhibition of DNA replication by aphidicolin prevented induction of RPA-p34 hyperphosphorylation by UV radiation. We postulate that this pathway is triggered by the accumulation of aberrant DNA replication intermediates, resulting from DNA replication fork blockage by UV photoproducts. Further, we suggest that RPA-p34 is hyperphosphorylated as a participant in the recombinational postreplication repair of these replication products. Successful resolution of these replication intermediates reduces the accumulation of chromosomal aberrations that would otherwise occur as a consequence of UV radiation.