Inflammaging: Age and Systemic, Cellular, and Nuclear Inflammatory Biology in Older Adults.

Systemic inflammation is associated with increasing age. Yet, there are limited data about the association between age and systemic inflammation within older adults, and whether older age is also associated with cellular and nuclear signaling markers of inflammation. In community-dwelling older adults (N = 262, 60-88 years), systemic levels of C-reactive protein, interleukin-6, and soluble tumor necrosis factor receptor II; levels of toll-like receptor-4-stimulated monocytic production of interleukin-6 and tumor necrosis factor α; and resting nuclear levels of activated nuclear factor kappa B and signal transducer and activator of transcription (STAT1, STAT3, STAT5) were evaluated. Adjusting for demographic and clinical factors, multivariate linear regression tested the association between age and each inflammatory marker. Age was positively associated with increased levels of interleukin-6 and soluble tumor necrosis factor receptor II (p's < .05) and with increases in STAT1, STAT3, and STAT5 activation (p's < .05). However, no relationship was found between age and C-reactive protein, toll-like receptor-4-stimulated interleukin-6/tumor necrosis factor alpha α production, or nuclear factor kappa B. Within a community-dwelling sample of older adults, older age is associated with increases in STAT activation, along with increases of systemic inflammatory cytokines. In older adults, heterogeneity in age-related increases in inflammatory disease risk may be related to individual variability in inflammation.

Racial/Ethnic Differences in Expectations Regarding Aging Among Older Adults.

Purpose of the Study: The study identifies differences in age-expectations between older adults from Korean, Chinese, Latino, and African American backgrounds living in the United States. Design and Methods: This study uses baseline demographic, age-expectation, social, and health data from 229 racial/ethnic minority seniors in a stroke-prevention intervention trial. Unadjusted regression models and pair-wise comparisons tested for racial/ethnic differences in age-expectations, overall, and across domain subscales (e.g., physical-health expectations). Adjusted regression models tested whether age-expectations differed across racial/ethnic groups after controlling for demographic, social, and health variables. Regression and negative binomial models tested whether age-expectations were consistently associated with health and well-being across racial/ethnic groups. Results: Age-expectations differed by race/ethnicity, overall and for each subscale. African American participants expected the least age-related functional decline and Chinese American participants expected the most decline. Although African American participants expected less decline than Latino participants in unadjusted models, they had comparable expectations adjusting for education. Latino and African American participants consistently expected less decline than Korean and Chinese Americans. Acculturation was not consistently related to age-expectations among immigrant participants over and above ethnicity. Although some previously observed links between expectations and health replicated across racial/ethnic groups, in adjusted models age-expectations were only related to depression for Latino participants. Implications: With a growing racial/ethnic minority older population in the United States, it is important to note older adults' age-expectations differ by race/ethnicity. Moreover, expectation-health associations may not always generalize across diverse samples.

Partial sleep deprivation activates the DNA damage response (DDR) and the senescence-associated secretory phenotype (SASP) in aged adult humans.

Age-related disease risk has been linked to short sleep duration and sleep disturbances; however, the specific molecular pathways linking sleep loss with diseases of aging are poorly defined. Key cellular events seen with aging, which are thought to contribute to disease, may be particularly sensitive to sleep loss. We tested whether one night of partial sleep deprivation (PSD) would increase leukocyte gene expression indicative of DNA damage responses (DDR), the senescence-associated secretory phenotype (SASP), and senescence indicator p16(INK4a) in older adult humans, who are at increased risk for cellular senescence. Community-dwelling older adults aged 61-86years (n=29; 48% male) underwent an experimental partial sleep deprivation (PSD) protocol over 4 nights, including adaptation, an uninterrupted night of sleep, partial sleep deprivation (sleep restricted 3-7AM), and a subsequent full night of sleep. Blood samples were obtained each morning to assess peripheral blood mononuclear cell (PBMC) gene expression using Illumina HT-12 arrays. Analyses of microarray results revealed that SASP (p<.05) and DDR (p=.08) gene expression were elevated from baseline to PSD nights. Gene expression changes were also observed from baseline to PSD in NFKB2, NBS1 and CHK2 (all p's<.05). The senescence marker p16(INK4a) (CDKN2A) was increased 1day after PSD compared to baseline (p<.01), however confirmatory RT-PCR did not replicate this finding. One night of partial sleep deprivation activates PBMC gene expression patterns consistent with biological aging in this older adult sample. PSD enhanced the SASP and increased the accumulation of damage that initiates cell cycle arrest and promotes cellular senescence. These findings causally link sleep deprivation to the molecular processes associated with biological aging.

Cognitive behavioral therapy and tai chi reverse cellular and genomic markers of inflammation in late-life insomnia: a randomized controlled trial.

BACKGROUND: Sleep disturbance is associated with activation of systemic and cellular inflammation, as well as proinflammatory transcriptional profiles in circulating leukocytes. Whether treatments that target insomnia-related complaints might reverse these markers of inflammation in older adults with insomnia is not known. METHODS: In this randomized trial, 123 older adults with insomnia were randomly assigned to cognitive-behavioral therapy for insomnia (CBT-I), tai chi chih (TCC), or sleep seminar education active control condition for 2-hour sessions weekly over 4 months with follow-up at 7 and 16 months. We measured C-reactive protein (CRP) at baseline and months 4 and 16; toll-like receptor-4 activated monocyte production of proinflammatory cytokines at baseline and months 2, 4, 7, and 16; and genome-wide transcriptional profiling at baseline and month 4. RESULTS: As compared with sleep seminar education active control condition, CBT-I reduced levels of CRP (months 4 and 16, ps < .05), monocyte production of proinflammatory cytokines (month 2 only, p < .05), and proinflammatory gene expression (month 4, p < .01). TCC marginally reduced CRP (month 4, p = .06) and significantly reduced monocyte production of proinflammatory cytokines (months 2, 4, 7, and 16; all ps < .05) and proinflammatory gene expression (month 4, p < .001). In CBT-I and TCC, TELiS promoter-based bioinformatics analyses indicated reduced activity of nuclear factor-κB and AP-1. CONCLUSIONS: Among older adults with insomnia, CBT-I reduced systemic inflammation, TCC reduced cellular inflammatory responses, and both treatments reduced expression of genes encoding proinflammatory mediators. The findings provide an evidence-based molecular framework to understand the potential salutary effects of insomnia treatment on inflammation, with implications for inflammatory disease risk.

Sleep loss activates cellular inflammation and signal transducer and activator of transcription (STAT) family proteins in humans.

Sleep disturbance and short sleep duration are associated with inflammation and related disorders including cardiovascular disease, arthritis, diabetes mellitus, and certain cancers. This study was undertaken to test the effects of experimental sleep loss on spontaneous cellular inflammation and activation of signal transducer and activator of transcription (STAT) family proteins, which together promote an inflammatory microenvironment. In 24 healthy adults (16 females; 8 males), spontaneous production of IL-6 and TNF-α in monocytes and spontaneous intranuclear expression of activated STAT1, STAT3, and STAT5 in peripheral blood mononuclear cells (PBMC), monocyte-, and lymphocyte populations were measured in the morning after uninterrupted baseline sleep, partial sleep deprivation (PSD, sleep period from 3a.m. to 7a.m.), and recovery sleep. Relative to baseline, spontaneous monocytic expression of IL-6 and TNF-α was significantly greater after PSD (P<0.02) and after recovery sleep (P<0.01). Relative to baseline, spontaneous monocytic expression of activated STAT1 and STAT5 was significantly greater after recovery sleep (P<0.007 and P<0.02, respectively) but not STAT3 (P=0.09). No changes in STAT1, STAT3, or STAT5 were found in lymphocyte populations. Sleep loss induces activation of spontaneous cellular innate immunity and of STAT family proteins, which together map the dynamics of sleep loss on the molecular signaling pathways that regulate inflammatory and other immune responses. Treatments that target short sleep duration have the potential to constrain inflammation and reduce the risk for inflammatory disorders and some cancers in humans.

Sleep deprivation and divergent toll-like receptor-4 activation of cellular inflammation in aging.

OBJECTIVES: Sleep disturbance and aging are associated with increases in inflammation, as well as increased risk of infectious disease. However, there is limited understanding of the role of sleep loss on age-related differences in immune responses. This study examines the effects of sleep deprivation on toll-like receptor activation of monocytic inflammation in younger compared to older adults. DESIGN, SETTING, AND PARTICIPANTS: Community-dwelling adults (n = 70) who were categorized as younger (25-39 y old, n = 21) and older (60-84 y old, n = 49) participants, underwent a sleep laboratory-based experimental partial sleep deprivation (PSD) protocol including adaptation, an uninterrupted night of sleep, sleep deprivation (sleep restricted to 03:00-07:00), and recovery. MEASUREMENT AND RESULTS: Blood samples were obtained each morning to measure toll-like receptor-4 activation of monocyte intracellular production of the inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Partial sleep deprivation induced a significant increase in the production of IL-6 and/or TNF-α that persisted after a night of recovery sleep (F(2,121.2) = 3.8, P < 0.05). Age moderated the effects of sleep loss, such that younger adults had an increase in inflammatory cytokine production that was not present in older adults (F(2,121.2) = 4.0, P < 0.05). CONCLUSION: Older adults exhibit reduced toll-like receptor 4 stimulated cellular inflammation that, unlike in younger adults, is not activated after a night of partial sleep loss. Whereas sleep loss increases cellular inflammation in younger adults and may contribute to inflammatory disorders, blunted toll-like receptor activation in older adults may increase the risk of infectious disease seen with aging.

Cognitive behavioral therapy vs. Tai Chi for late life insomnia and inflammatory risk: a randomized controlled comparative efficacy trial.

STUDY OBJECTIVES: To investigate the comparative efficacy of cognitive behavioral therapy (CBT), Tai Chi Chih (TCC), and sleep seminar education control (SS) on the primary outcome of insomnia diagnosis, and secondary outcomes of sleep quality, fatigue, depressive symptoms, and inflammation in older adults with insomnia. DESIGN: Randomized controlled, comparative efficacy trial. SETTING: Los Angeles community. PATIENTS: 123 older adults with chronic and primary insomnia. INTERVENTIONS: Random assignment to CBT, TCC, or SS for 2-hour group sessions weekly over 4 months with follow-up at 7 and 16 months. MEASUREMENTS: Insomnia diagnosis, patient-reported outcomes, polysomnography (PSG), and high-sensitivity C-reactive protein (CRP) levels. RESULTS: CBT performed better than TCC and SS in remission of clinical insomnia as ascertained by a clinician (P < 0.01), and also showed greater and more sustained improvement in sleep quality, sleep parameters, fatigue, and depressive symptoms than TCC and SS (all P values < 0.01). As compared to SS, CBT was associated with a reduced risk of high CRP levels (> 3.0 mg/L) at 16 months (odds ratio [OR], 0.26 [95% CI, 0.07-0.97] P < 0.05). Remission of insomnia was associated with lower levels of CRP (P < 0.05) at 16 months. TCC was associated with improvements in sleep quality, fatigue, and depressive symptoms as compared to SS (all P's < 0.05), but not insomnia remission. PSG measures did not change. CONCLUSIONS: Treatment of late-life insomnia is better achieved and sustained by cognitive behavioral therapies. Insomnia treatment and remission reduces a marker of inflammatory risk, which has implications for cardiovascular morbidity and diabetes observed with sleep disturbance in epidemiologic surveys.

Tai chi, cellular inflammation, and transcriptome dynamics in breast cancer survivors with insomnia: a randomized controlled trial.

BACKGROUND: Mind-body therapies such as Tai Chi are widely used by breast cancer survivors, yet effects on inflammation are not known. This study hypothesized that Tai Chi Chih (TCC) would reduce systemic, cellular, and genomic markers of inflammation as compared with cognitive behavioral therapy for insomnia (CBT-I). METHODS: In this randomized trial for the treatment of insomnia, 90 breast cancer survivors with insomnia were assigned to TCC or CBT-I for 2-hour sessions weekly for 3 months. At baseline and postintervention, blood samples were obtained for measurement of C-reactive protein and toll-like receptor-4-activated monocyte production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF), with a random subsample (n = 48) analyzed by genome-wide transcriptional profiling. RESULTS: Levels of C-reactive protein did not change in the TCC and CBT-I groups. Levels of toll-like receptor-4-activated monocyte production of IL-6 and TNF combined showed an overall reduction in TCC versus CBT-I (P < .02), with similar effects for IL-6 (P = .07) and TNF (P < .05) alone. For genome-wide transcriptional profiling of circulating peripheral blood mononuclear cells, expression of genes encoding proinflammatory mediators showed an overall reduction in TCC versus CBT-I (P = .001). TELiS promoter-based bioinformatics analyses implicated a reduction of activity of the proinflammatory transcription factor, nuclear factor-κB, in structuring these differences. CONCLUSIONS: Among breast cancer survivors with insomnia, 3 months of TCC reduced cellular inflammatory responses, and reduced expression of genes encoding proinflammatory mediators. Given the link between inflammation and cancer, these findings provide an evidence-based molecular framework to understand the potential salutary effects of TCC on cancer survivorship.

Acute painful stress and inflammatory mediator production.

BACKGROUND: Proinflammatory pathways may be activated under conditions of painful stress, which is hypothesized to worsen the experience of pain and place medically vulnerable populations at risk for increased morbidity. OBJECTIVES: To evaluate the effects of pain and subjective pain-related stress on proinflammatory activity. METHODS: A total of 19 healthy control subjects underwent a single standard cold-pressor pain test (CPT) and a no-pain control condition. Indicators of pain and stress were measured and related to inflammatory immune responses [CD8+ cells expressing the integrin molecule CD11a (CD811a), interleukin (IL)-1 receptor agonist (IL-1RA), and IL-6] immediately following the painful stimulus and compared to responses under no-pain conditions. Heart rate and mean arterial pressure were measured as indicators of sympathetic stimulation. RESULTS: CPT was clearly painful and generated an activation of the sympathetic nervous system. CD811a increased in both conditions, but with no statistically significantly greater increase following CPT (p<0.06). IL-1RA demonstrated a non-statistically significant increase following CPT (p<0.07). The change in IL-6 following CPT differed significantly from the response seen in the control condition (p<0.02). CONCLUSIONS: These findings suggest that CP acute pain may affect proinflammatory pathways, possibly through mechanisms related to adrenergic activation.