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Biological aging is associated with progressive damage accumulation, loss of organ reserves, and systemic inflammation ('inflammaging'), which predispose for a wide spectrum of chronic diseases, including several types of cancer. In contrast, aerobic exercise training (AET) reduces inflammation, lowers all-cause mortality, and enhances both health and lifespan. In this study, we examined the benefits of early-onset, lifelong AET on predictors of health, inflammation, and cancer incidence in a naturally aging mouse model (C57BL/J6). Lifelong, voluntary wheel-running (O-AET; 26-month-old) prevented age-related declines in aerobic fitness and motor coordination vs. age-matched, sedentary controls (O-SED). AET also provided partial protection against sarcopenia, dynapenia, testicular atrophy, and overall organ pathology, hence augmenting the 'physiologic reserve' of lifelong runners. Systemic inflammation, as evidenced by a chronic elevation in 17 of 18 pro- and anti-inflammatory cytokines and chemokines (P < 0.05 O-SED vs. 2-month-old Y-CON), was potently mitigated by lifelong AET (P < 0.05 O-AET vs. O-SED), including master regulators of the cytokine cascade and cancer progression (IL-1β, TNF-α, and IL-6). In addition, circulating SPARC, previously known to be upregulated in metabolic disease, was elevated in old, sedentary mice, but was normalized to young control levels in lifelong runners. Remarkably, malignant tumours were also completely absent in the O-AET group, whereas they were present in the brain (pituitary), liver, spleen, and intestines of sedentary mice. Collectively, our results indicate that early-onset, lifelong running dampens inflammaging, protects against multiple cancer types, and extends healthspan of naturally-aged mice.

S9 Table is omitted from the list of Supporting Information. Supporting information LifeLong I Heart mRNA. Skip to file navigationSkip to generic navigation A B C D E F G H I J K L M N O P Q R S T U V W X Y Z AA AB AC AD AE AF AG AH AI AJ AK AL AM AN AO AP AQ AR AS AT AU AV AW AX 1 Plate 1 Raw CT values Average delta CT ΔCT 2 Gene ↓ Subject → S8.1 S24 S9.3 S6.4 S9.1 Y18 Y25 Y19 Y9 Gene ↓ S8.1 S24 S9.3 S6.4 S9.1 Y18 Y25 Y19 Y9 S8.1 S24 S9.3 S6.4 S9.1 Y18 Y25 3 GAPDH A 17.2227584197101 17.0960169111601 17.1450399266626 17.2261195007261 17.2124745053596 16.9728519295508 17.3746878619056 17.4504414950499 17.1233350547625 17.0068797617316 17.1670375618892 17.0066086089542 17.2249380779292 16.9480574830836 16.143782730167 16.2069201529908 16.8567610725968 16.3439680391188 GAPDH 17.159387665435098 17.185579713694352 17.0926632174552 17.41256467847775 17.06510740824705 17.0868230854217 17.0864977805064 16.1753514415789 16.6003645558578 Housekeeper GAPDH 4 IL-6 B 31.2832774422591 31.235382455168 30.2525150817788 29.9037571204569 31.6058739365401 31.9775533045845 27.9692968107875 27.9982552939548 32.7702831691699 33.7756423941107 28.2279066586806 28.0454943907626 31.386558277345 31.7741916616727 30.3798453818442 30.3087536324683 32.9874743823418 32.8994165659944 IL-6 31.25932994871355 30.07813610111785 31.791713620562298 27.983776052371148 33.2729627816403 28.136700524721597 31.58037496950885 30.34429950715625 32.9434454741681 14.099942283278452 12.892556387423497 14.699050403107098 10.571211373893398 16.20785537339325 11.049877439299898 14.49387718900245 5 IL-1b C 27.7607610399024 28.0818057660842 29.2743824258867 29.0258717700794 29.4553611635112 29.2098723094273 28.6113257800381 28.9045331522702 30.7655600970071 31.0763075351084 30.0488085335771 29.7378195063969 28.3498373549533 28.3655445868964 30.4028544981929 30.2303532089152 30.4824451280281 30.562068913743 IL-1b 27.9212834029933 29.150127097983052 29.332616736469248 28.757929466154152 30.920933816057747 29.893314019987 28.35769097092485 30.31660385355405 30.52225702088555 10.761895737558202 11.9645473842887 12.239953519014048 11.345364787676402 13.855826407810696 12.8064909345653 11.271193190418451 6 IL-18 D 31.0242427859449 30.8631544198324 30.6976407996928 29.8345660968711 30.32994861068 30.3145546343817 27.7622969217847 27.6972954924814 30.5621005433449 30.718048359783 29.7132291328988 29.8871056810122 30.4645477381786 30.5593651611927 29.1422958771514 29.0787128186274 31.8903661393288 32.0048169676586 IL-18 30.943698602888652 30.26610344828195 30.32225162253085 27.72979620713305 30.64007445156395 29.800167406955502 30.51195644968565 29.110504347889403 31.9475915534937 13.784310937453554 13.080523734587597 13.22958840507565 10.317231528655299 13.5749670433169 12.713344321533803 13.42545866917925 7 NFKb-1 E 24.8254567305921 25.1348088185582 25.0062082930937 24.5186512654426 24.8872569734572 24.779394225765 24.1319627569722 24.0011813531246 24.4887046419295 24.6995725596868 24.3820148457641 24.3865172414558 24.5644210615383 24.6691290358862 24.2274232660528 24.0889242450612 25.0731850378707 24.6953365937736 NFKb-1 24.98013277457515 24.76242977926815 24.8333255996111 24.0665720550484 24.59413860080815 24.384266043609948 24.61677504871225 24.158173755557 24.884260815822152 7.820745109140052 7.576850065573797 7.7406623821559 6.65400737657065 7.529031192561099 7.297442958188249 7.53027726820585 8 NFkb-2 F 26.7045516920118 26.6757345804755 26.7646421207714 26.8003272797153 26.6759706329691 27.0759950868447 25.8618089955849 26.1801295324672 27.1202851729312 27.0835233764581 26.2010221629559 26.2986877952507 26.3336393871413 26.4945753531329 25.7828308451832 25.9383731474701 27.3708254452238 26.9787996700945 NFkb-2 26.69014313624365 26.78248470024335 26.875982859906898 26.02096926402605 27.10190427469465 26.2498549791033 26.4141073701371 25.86060199632665 27.174812557659152 9.53075547080855 9.596904986549 9.783319642451698 8.6084045855483 10.036796866447599 9.163031893681602 9.3276095896307 9 Cdkn1a G 24.5507361616066 25.3559147556468 24.6079147431688 25.1782502986826 25.2563040633391 25.1598136456992 24.4294896036426 24.5228059376776 26.4031158122344 26.1242908123156 24.5802551734152 24.6413624043314 24.4282269326323 24.1965984515812 25.2088295538285 25.0528520694569 25.3329599581332 24.8160728889468 Cdkn1a 24.9533254586267 24.8930825209257 25.20805885451915 24.4761477706601 26.263703312275 24.6108087888733 24.312412692106747 25.1308408116427 25.074516423539997 7.793937793191603 7.7075028072313465 8.115395637063951 7.063583092182348 9.198595904027947 7.523985703451601 7.2259149116003485 10 CDKn2a H 31.4164200969947 31.0429903524676 31.2079072243556 31.4143918034498 31.934769607 32.5200067014273 30.9810559840924 31.187906600095 31.5622914271198 31.6594025383255 33.7404204593239 33.0560980126742 33.3737262937795 33.5228506413887 32.6502542170308 33.0616429880405 34.722677748124 35.0908853816313 CDKn2a 31.22970522473115 31.3111495139027 32.22738815421365 31.0844812920937 31.61084698272265 33.39825923599905 33.4482884675841 32.85594860253565 34.90678156487765 14.07031755929605 14.125569800208346 15.134724936758449 13.671916613615949 14.545739574475597 16.31143615057735 16.3617906870777 11 CXCL1 I 28.7206322985985 28.9339128995328 28.3298871415528 28.0462166079446 29.1076582245152 29.2643337952645 29.6820397705059 29.3485383661744 29.6849346064857 29.9287287583586 29.3483864108378 29.3275096675003 29.0009619306224 29.3668816551351 29.2808715089445 29.327670178107 30.649263415718 30.4691555624855 CXCL1 28.82727259906565 28.1880518747487 29.18599600988985 29.51528906834015 29.80683168242215 29.33794803916905 29.18392179287875 29.30427084352575 30.55920948910175 11.667884933630553 11.00247216105435 12.093332792434648 12.102724389862399 12.741724274175098 12.25112495374735 12.09742401237235 12 Stat3 J 26.0904890379949 25.9328304379032 25.9063931310091 26.1329342458923 26.4609068410479 26.4297398050048 25.7018593565636 24.9656464528592 26.0560010797303 25.8896903923348 25.1840850843387 25.3433284943611 25.7927734157918 25.6862456816375 24.7283906358084 25.0138247366201 26.1147216604091 25.8976191416658 Stat3 26.01165973794905 26.0196636884507 26.44532332302635 25.3337529047114 25.97284573603255 25.2637067893499 25.73950954871465 24.871107686214252 26.00617040103745 8.852272072513951 8.834083974756346 9.35266010557115 7.9211882262336495 8.907738327785498 8.176883703928201 8.653011768208252 13 TNF-a K 30.1073341921065 30.5360636345848 30.2260615221732 29.9559067650374 29.2464199480057 29.1643666740457 28.6089768107746 28.79978930134 29.6793392945751 29.1310263213341 29.9822045453806 29.6659316486985 30.7461596433001 30.2097075953468 29.6386111561683 29.709346427943 30.1151871528581 29.8693295774509 TNF-a 30.32169891334565 30.0909841436053 29.2053933110257 28.7043830560573 29.405182807954603 29.82406809703955 30.47793361932345 29.67397879205565 29.9922583651545 13.162311247910552 12.905404429910948 12.112730093570498 11.291818377579549 12.340075399707551 12.737245011617851 13.391435838817053 14 Casp1 L 27.2033919131097 27.6744363531269 26.5802828002749 26.2281642714393 26.4250342743884 26.7102082676285 25.6336464042801 25.5547383413519 27.0678362649028 27.0065083778922 27.2463448661041 27.1608443954414 27.35798527279 27.3796265798296 26.627225712546 26.8875428314112 27.5112526099685 27.5986345348855 Casp1 27.438914133118303 26.4042235358571 26.56762127100845 25.594192372816 27.0371723213975 27.20359463077275 27.3688059263098 26.7573842719786 27.554943572427 10.279526467683205 9.218643822162747 9.474958053553248 8.18162769433825 9.972064913150447 10.11677154535105 10.282308145803402 15 NEK7 M 23.9685847278823 24.5433164196844 23.43572321289 23.9081916995917 23.5086828809897 23.5270279353252 23.2133882975186 23.2757457924196 23.3805267633634 23.5192038087196 23.1886907682083 23.4814557673291 23.358820269235 24.1215698673907 22.9541524276427 22.8534133014146 23.7893714938226 23.5573365389361 NEK7 24.25595057378335 23.67195745624085 23.517855408157452 23.2445670449691 23.4498652860415 23.3350732677687 23.74019506831285 22.90378286452865 23.67335401637935 7.09656290834825 6.486377742546498 6.425192190702251 5.8320023664913485 6.384757877794449 6.248250182347 6.653697287806452 16 NLRP3 N 30.244118458751 29.5369897211229 30.3603582591055 30.2503268831856 29.4758591262319 29.4736269640112 29.3352875367771 29.320653238761 30.26 30.1814655814764 31.146281441585 30.6535936006003 29.45 29.6706759432538 29.7277413856785 29.6453588719767 32.0548305999839 31.4854419974249 NLRP3 29.89055408993695 30.30534257114555 29.47474304512155 29.32797038776905 30.2207327907382 30.89993752109265 29.5603379716269 29.686550128827598 31.7701362987044 12.73116642450185 13.1197628574512 12.382079827666349 11.9154057092913 13.155625382491149 13.81311443567095 12.473840191120502 17 ASC O 26.9861347390865 27.0521925568865 27.534747032205 26.6997139959596 27.0828035675481 27.0235988480711 25.8575043892974 26.0087951630763 26.696034618544 27.1135738040462 26.1538464899565 26.0982055323081 26.9292364798881 26.7892820090882 25.841950717191 25.4027055290128 27.1753237657249 27.1722998114956 ASC 27.0191636479865 27.1172305140823 27.0532012078096 25.933149776186852 26.9048042112951 26.1260260111323 26.85925924448815 25.6223281231019 27.17381178861025 9.859775982551401 9.93165080038795 9.9605379903544 8.520585097709102 9.83969680304805 9.039202925710601 9.772761463981752 18 SPARC P 22.4062672259926 22.5213462994263 22.1406264428644 22.1952706102821 22.3852686414166 23.3004426221895 20.7103936770761 21.0545135691509 22.0901620956444 22.4793107093598 22.6866619438751 21.6821678981581 22.3 21.6934115711809 21.0815559489363 21.0559757672406 22.1297187073265 21.8817057286147 SPARC 22.46380676270945 22.167948526573248 22.84285563180305 20.8824536231135 22.284736402502098 22.1844149210166 21.99670578559045 21.068765858088447 22.0057122179706 5.3044190972743515 4.982368812878896 5.7501924143478504 3.4698889446357484 5.21962899425

Objective: Irritability is common in pediatric autism spectrum disorder (ASD) patients. This can have major implications in child development, receptivity to behavioral therapy, as well as child and caregiver well-being. A systematic review and network meta-analysis were conducted to assess the efficacy and safety of atypical antipsychotics in treating irritability in these patients. Methods: Studies were identified from Medline, Embase, and PsycINFO from inception to March 2018. The clinical trials database was reviewed. Studies were included if they were a double-blind, randomized controlled trial utilizing the Aberrant Behavior Checklist Irritability (ABC-I) to measure the efficacy of atypical antipsychotic monotherapy. Data extraction was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-analyses for network meta-analysis guidelines. The main outcome was the reduction in irritability score using the ABC-I subscale from baseline. Results: Eight trials comparing four interventions—risperidone, aripiprazole, lurasidone, and placebo in 878 patients, were included. Both risperidone and aripiprazole had significantly reduced ABC-I scores than placebo. Estimates of mean differences (95% credible intervals) were risperidone, −6.89 (−11.14, −2.54); aripiprazole, −6.62 (−10.88, −2.22); and lurasidone, −1.61 (−9.50, 6.23). Both risperidone and aripiprazole had similar safety. There were only eight studies included in the analysis, however, sample sizes were not small. Variance in reporting of adverse effects limited the quality of safety analysis. Conclusion: Risperidone and aripiprazole were the two best drugs, with comparable efficacy and safety in pediatric ASD patients. These two medications could be beneficial in improving irritability in these patients.