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The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1–3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5–7, and is established to increase healthy lifespan in multiple species8,9. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11–13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14–16 and contrasting with reports that biological aging may not be modifiable17. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18–20.

To investigate the association of cartilage thickness change over 24 months, as determined by magnetic resonance imaging (MRI), with knee osteoarthritis (OA) progression at 24-48 months.This nested case-control study included 600 knees with a baseline Kellgren/Lawrence (K/L) grade of 1-3 from 600 Osteoarthritis Initiative (OAI) participants. Case knees (n = 194) had both medial tibiofemoral radiographic joint space loss (≥0.7 mm) and a persistent increase in the Western Ontario and McMaster Universities Osteoarthritis Index pain score (≥9 on a 0-100 scale) 24-48 months from baseline. Control knees (n = 406) included 200 with neither radiographic nor pain progression, 103 with radiographic progression only, and 103 with pain progression only. Medial and lateral femorotibial cartilage was segmented from sagittal 3T MRIs at baseline, 12 months, and 24 months. Logistic regression was used to assess the association of change in cartilage thickness, with a focus on the central medial femorotibial compartment, and OA progression.Central medial femorotibial compartment thickness loss was significantly associated with case status, with an odds ratio (OR) of 1.9 (95% confidence interval [95% CI] 1.6-2.3) (P0.0001). Association with case status reached P0.05 for both the central femur (OR 1.8 [95% CI 1.5-2.2]) and the central tibia (OR 1.6 [95% CI 1.3-1.9]). Lateral femorotibial compartment cartilage thickness loss, in contrast, was not significantly associated with case status. A reduction in central medial femorotibial compartment cartilage thickness was strongly associated with radiographic progression (OR 4.0 [95% CI 2.9-5.3]; P0.0001) and only weakly associated with pain progression (OR 1.3 [95% CI 1.1-1.6]; P0.01).Our findings indicate that loss of medial femorotibial cartilage thickness over 24 months is associated with the combination of radiographic and pain progression in the knee, with a stronger association for radiographic progression.

Relapsing polychondritis (RP) is a rare and severe disease which may lead to destruction of elastic cartilages. Until now, no reliable biomarker of disease activity in RP has been available. This study was designed to measure serum levels of cartilage biomarkers during both active and inactive phases of the disease.Serum levels of cartilage oligomeric matrix protein (COMP), chondroitin sulfate 846 epitope (CS846) of proteoglycan aggrecan and collagen type II collagenase cleavage neoepitope (C2C) were measured retrospectively in 21 subjects with RP. The Wilcoxon matched-pairs signed-rank test was used for statistical comparisons of biomarker levels in active and inactive phases of RP.Only the serum level of COMP was significantly increased during disease flares. Steroids did not alter the serum cartilage-related biomarker levels. However, during the active phase, C2C levels were significantly higher in steroid treated patients compared with non-steroid treated patients.This study suggests that serum COMP level may be useful for monitoring disease activity of RP. Further prospective studies are required to confirm this result.

To determine the feasibility, safety, and potential clinical efficacy of intravenous (IV) doxycycline therapy for rheumatoid arthritis (RA), as well as its possible effects on serum and urinary markers of collagen breakdown.The exploratory trial was designed as a 16-week, single-center, randomized, double-blind, placebo-controlled trial. Eligible subjects with active seropositive or erosive RA were randomly allocated into 3 treatment groups: doxycycline 200 mg IV, azithromycin 250 mg orally, or placebo. The blinded IV study drug was administered once daily for the first 3 weeks by home self-infusion and then weekly for the next 8 weeks, concurrent with the blinded oral study drug at the prescribed doses. The primary end points were the change between baseline and week 4 in the tender joint count, erythrocyte sedimentation rate, and urinary excretion of pyridinoline.The trial was stopped prematurely after enrollment of 31 patients. Three subjects were withdrawn because of worsening arthritis, and 1 patient was withdrawn when newly diagnosed with breast cancer. Infusion-related events occurred in 13 (42%) of 31 patients, but none were serious. There were 4 serious adverse events unrelated to the study drug, including a new diagnosis of breast cancer in 3 cases and hospitalization for abdominal pain in 1 case. No significant differences were observed across treatment groups in any of the 3 primary clinical end points.Although IV doxycycline therapy was generally well-tolerated by patients in this trial, it did not show any evidence of reducing disease activity or collagen crosslink production.

To characterize serum cartilage oligomeric matrix protein (COMP) levels by age and gender for a radiographically defined population free of hip and knee osteoarthritis (OA), and to examine the potential utility of COMP as a diagnostic biomarker for knee OA.Serum samples and knee and hip radiographs were obtained at a baseline evaluation as part of the Johnston County Osteoarthritis Project, a population-based study of OA in rural North Carolina. A total of 291 Caucasian participants were randomly selected for COMP analysis, 143 patients with radiographic knee OA (Kellgren/Lawrence [K/L] gradeor = 2) and 148 controls with neither hip nor knee OA (K/L grade 0), evenly distributed by age and gender. COMP was quantified by competitive enzyme-linked immunosorbent assay with monoclonal antibody 17-C10. The natural log-transformed COMP data were analyzed using general linear models.Serum COMP levels were significantly elevated (P = 0.0001) in the ageor = 65 group (mean +/- SD 1,302.1 +/- 496.7 ng/ml) versus the age 45-54 and age 55-64 groups (1,058.1 +/- 432.4 and 1,038.6 +/- 313.3, respectively). Serum COMP levels of the OA group were significantly higher than those of the control group (1,208.57 +/- 487.47 ng/ml versus 1,061.83 +/- 370.58 ng/ml; P = 0.0093). Serum COMP levels also increased significantly with knee OA K/L grade (P = 0.0047), knee OA laterality (P = 0.0043), and number of knee and hip joints involved (P = 0.0001). There was no significant difference in serum COMP levels by gender or obesity.We demonstrate that in a population-based sample, serum COMP levels can distinguish an OA-affected subgroup from an unaffected subgroup and can reflect disease severity and multiple joint involvement in OA.

To analyze the in vivo compartmental expression of collagenases 1 and 3 (MMP-1 and MMP-13) in the Hartley guinea pig model of spontaneously occurring osteoarthritis (OA) for the purpose of elucidating their roles in the pathogenesis of OA.Competitive reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry quantification of messenger RNA (mRNA) and protein levels in medial and lateral tibial cartilage obtained from the knee joints of 2-month-old (no OA) and 12-month-old (OA) guinea pigs.The patterns of mRNA expression of collagenases 1 and 3 varied with the age of the animal and the compartment of the knee. We also found focal areas of collagenase 1 and collagenase 3 proteins localized to the extracellular matrix of OA lesion sites, coincident with three-quarter/one-quarter collagen cleavage. Collagenase 3 protein was also abundant throughout the medial tibial cartilage of 2-month-old animals.This represents the first description of bona fide collagenase 1 in a rodent species. Recent evidence, however, based on analysis of mitochondrial DNA homologies, suggests that the guinea pig is not a member of the order Rodentia and may be more closely allied with lagomorphs. This taxonomic controversy leaves open to question the issue of the expression of collagenase 1 in other rodents, such as mice and rats. The presence of active collagenases 1 and 3 at OA lesion sites is consistent with an important role of these enzymes in the cartilage degradation of OA in guinea pigs. The expression of collagenase 3 in medial tibial cartilage from 2-month-old guinea pigs may signify a role of this enzyme in cartilage remodeling with growth and development, or it may represent an early molecular manifestation of OA.

We describe a hypogammaglobulinemic man with erosive oligoarticular septic arthritis due to Ureaplasma urealyticum. His clinical course was complicated by a subcutaneous abscess. Multiple synovial cultures were negative until finally cultures specific for mycoplasmas were performed. Serologic diagnosis cannot be relied upon in hypogammaglobulinemic patients because they do not mount a perceptible antibody response. This underscores the importance of a high clinical suspicion of mycoplasmas as etiologic agents of septic arthritis in this population and early communication with the microbiology laboratory so that appropriate cultures for mycoplasmas can be performed and joint destruction minimized.