Marmoset as a model to study kidney changes associated with aging.
Lee HJ, Gonzalez O, Dick EJ Jr, Donati A, Feliers D, Goutam Ghosh C, Ross C, Venkatachalam M, Tardif SD, Kasinath BS
J Gerontol A Biol Sci Med Sci. 2018 Oct 13. doi: 10.1093/gerona/gly237. [Epub ahead of print]
We evaluated whether the marmoset, a nonhuman primate, can serve as a good model to study aging related changes in the kidney by employing healthy young and aged marmosets of both sexes. Aging was associated with glomerulosclerosis, interstitial fibrosis and arteriolosclerosis in both sexes; correspondingly, the content of matrix proteins was increased. Functionally, aging resulted in an increase in urinary albumin and protein excretion. There was a robust correlation between markers of fibrosis and functional changes. We explored signaling pathways as potential mechanistic events. Aging in males, but not in females, was associated with reduced renal cortical activity of AMP-activated protein kinase (AMPK) and a trend toward activation of mechanistic target of rapamycin complex 1 (mTORC1); upstream of AMPK and mTORC1, Akt and IGF-1 receptor were activated. In both sexes, aging promoted kidney activation of transforming growth factor β-1 signaling pathway. While the expression of cystathionine β-synthase (CBS), an enzyme involved hydrogen sulfide (H2S) synthesis, was reduced in both aged males and females, decreased H2S generation was seen in only males. Our studies show that the marmoset is a valid model to study kidney aging; some of the signaling pathways involved in renal senescence differ between male and female marmosets.
Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets.
Sills AM, Artavia JM, DeRosa BD, Ross CN, Salmon AB
American Journal of Primatology. 2018 Oct 12:e22927. doi: 10.1002/ajp.22927. [Epub ahead of print].
Interventions to extend lifespan and improve health with increasing age would have significant impact on a growing aged population. There are now several pharmaceutical interventions that extend lifespan in laboratory rodent models with rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR) being the most well studied. In this study, we report on the hematological effects in a cohort of middle-aged common marmosets (Callithrix jacchus) that were enrolled in a study to test the effects of daily rapamycin treatment on aging in this species. In addition, we assessed whether sex was a significant factor in either baseline assessment or as an interaction with rapamycin treatment. Among our cohort at baseline, we found few differences in either basic morphology or hematological markers of blood cell counts, metabolism or inflammation between male and female marmosets. After dosing with rapamycin, surprisingly we found trough blood concentrations of rapamycin were significantly lower in female compared to male marmosets. Despite this pharmacological difference, both sexes had only minor changes in cellular blood counts after 9 months of rapamycin. These data then suggest that the potential clinical hematological side effects of rapamycin are not likely outcomes of long-term rapamycin in relatively healthy, middle-aged marmosets.
Tau protein aggregation is associated with cellular senescence in the brain.
Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q, Orr ME
Aging Cell. 2018 Dec;17(6):e12840. doi: 10.1111/acel.12840. Epub 2018 Oct 11.
Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI), and over twenty others. Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss (Arriagada, Growdon, Hedley-Whyte, & Hyman, ), yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis (de Calignon, Spires-Jones, Pitstick, Carlson, & Hyman, 2009), which suggests that secondary mechanisms are driving toxicity. Transcriptomic analyses of NFT-containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction. Using four AD transgenic mouse models, we found that NFTs, but not Aβ plaques, display a senescence-like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late-stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.
Hydrogen sulfide ameliorates aging-associated changes in the kidney.
Lee HJ, Feliers D, Barnes JL, Oh S, Choudhury GG2, Diaz V, Galvan V, Strong R, Nelson J, Salmon A, Kevil CG, Kasinath BS
Geroscience. 2018 Apr;40(2):163-176. doi: 10.1007/s11357-018-0018-y. Epub 2018 May 1.
Aging is associated with replacement of normal kidney parenchyma by fibrosis. Because hydrogen sulfide (H2S) ameliorates kidney fibrosis in disease models, we examined its status in the aging kidney. In the first study, we examined kidney cortical H2S metabolism and signaling pathways related to synthesis of proteins including matrix proteins in young and old male C57BL/6 mice. In old mice, increase in renal cortical content of matrix protein involved in fibrosis was associated with decreased H2S generation and AMPK activity, and activation of insulin receptor (IR)/IRS-2-Akt-mTORC1-mRNA translation signaling axis that can lead to increase in protein synthesis. In the second study, we randomized 18-19 month-old male C57BL/6 mice to receive 30 μmol/L sodium hydrosulfide (NaHS) in drinking water vs. water alone (control) for 5 months. Administration of NaHS increased plasma free sulfide levels. NaHS inhibited the increase in kidney cortical content of matrix proteins involved in fibrosis and ameliorated glomerulosclerosis. NaHS restored AMPK activity and inhibited activation of IR/IRS-2-Akt-mTORC1-mRNA translation axis. NaHS inhibited age-related increase in kidney cortical content of p21, IL-1β, and IL-6, components of the senescence-associated secretory phenotype. NaHS abolished increase in urinary albumin excretion seen in control mice and reduced serum cystatin C levels suggesting improved glomerular clearance function. We conclude that aging-induced changes in the kidney are associated with H2S deficiency. Administration of H2S ameliorates aging-induced kidney changes probably by inhibiting signaling pathways leading to matrix protein synthesis.
A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects.
Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, Benavides AD, Curiel TJ, Javors MA, Musi N, Chiodo L, Koek W, Gelfond JAL, Kellogg DL Jr
Exp Gerontol. 2018 May;105:53-69. doi: 10.1016/j.exger.2017.12.026. Epub 2018 Feb 3.
Inhibition of the mechanistic target of rapamycin (mTOR) pathway by rapamycin (RAPA), an FDA-approved immunosuppressive drug used as a clinical therapy to prevent solid organ allograft rejection, enhances longevity in mice. Importantly, RAPA was efficacious even when initiated in relatively old animals, suggesting that mTOR inhibition could potentially slow the progression of aging-associated pathologies in older humans (Harrison et al., 2009; Miller et al., 2011). However, the safety and tolerability of RAPA in older human subjects have not yet been demonstrated. Towards this end, we undertook a placebo-controlled pilot study in 25 generally healthy older adults (aged 70-95 years); subjects were randomized to receive either 1 mg RAPA or placebo daily. Although three subjects withdrew, 11 RAPA and 14 controls completed at least 8 weeks of treatment and were included in the analysis. We monitored for changes that would indicate detrimental effects of RAPA treatment on metabolism, including both standard clinical laboratory assays (CBC, CMP, HbA1c) and oral glucose tolerance tests (OGTTs). We also monitored parameters typically associated with aging that could potentially be modified by RAPA; these included cognitive function which was assessed by three different tools: Executive Interview-25 (EXIT25); Saint Louis University Mental Status Exam (SLUMS); and Texas Assessment of Processing Speed (TAPS). In addition, physical performance was measured by handgrip strength and 40-foot timed walks. Lastly, changes in general parameters of healthy immune aging, including serum pro-inflammatory cytokine levels and blood cell subsets, were assessed. Five subjects reported potential adverse side effects; in the RAPA group, these were limited to facial rash (1 subject), stomatitis (1 subject) and gastrointestinal issues (2 subjects) whereas placebo treated subjects only reported stomatitis (1 subject). Although no other adverse events were reported, statistically significant decrements in several erythrocyte parameters including hemoglobin (HgB) and hematocrit (Hct) as well as in red blood cell count (RBC), red blood cell distribution width (RDW), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were observed in the RAPA-treatment group. None of these changes manifested clinically significant effects during the short duration of this study. Similarly, no changes were noted in any other clinical laboratory, cognitive, physical performance, or self-perceived health status measure over the study period. Immune parameters were largely unchanged as well, possibly due to the advanced ages of the cohort (70-93 years; mean age 80.5). RAPA-associated increases in a myeloid cell subset and in TREGS were detected, but changes in most other PBMC cell subsets were not statistically significant. Importantly, the OGTTs revealed no RAPA-induced change in blood glucose concentration, insulin secretion, and insulin sensitivity. Thus, based on the results of our pilot study, it appears that short-term RAPA treatment can be used safely in older persons who are otherwise healthy; a trial with a larger sample size and longer treatment duration is warranted.
The development of a specific pathogen free (SPF) barrier colony of marmosets (Callithrix jacchus) for aging research.
Ross CN, Austad S, Brasky K, Brown CJ, Forney LJ, Gelfond JA, Lanford R, Richardson A, Tardif SD
Aging (Albany NY). 2017 Dec 7;9(12):2544-2558. doi: 10.18632/aging.101340.
A specific pathogen free (SPF) barrier colony of breeding marmosets (Callithrix jacchus) was established at the Barshop Institute for Longevity and Aging Studies. Rodent and other animal models maintained as SPF barrier colonies have demonstrated improved health and lengthened lifespans enhancing the quality and repeatability of aging research. The marmosets were screened for two viruses and several bacterial pathogens prior to establishing the new SPF colony. Twelve founding animals successfully established a breeding colony with increased reproductive success, improved health parameters, and increased median lifespan when compared to a conventionally housed, open colony. The improved health and longevity of marmosets from the SPF barrier colony suggests that such management can be used to produce a unique resource for future studies of aging processes in a nonhuman primate model.
Proton pump inhibitor use associated with changes in gut microbiota composition.
Reveles KR, Ryan CN, Chan L, Cosimi RA, Haynes WL
Gut. 2018 Jul;67(7):1369-1370. doi: 10.1136/gutjnl-2017-315306. Epub 2017 Oct 9.
We read with great interest the recent publications in Gut by Imhann et al and Jackson et al, which assessed the impact of proton pump inhibitor (PPI) use on gut microbiota diversity and composition in humans. PPIs are one of the most commonly used drug classes worldwide. Once initiated, they are often used chronically without clear therapeutic intent. PPIs alter GI pH and delay gastric emptying rate, which could directly affect gut microbiota and survival of enteric pathogens. Using three independent cohorts (211 PPI users and 1604 non-users), Imhann et al reported a significant decrease in alpha diversity and changes in 20% of bacterial taxa in PPI users compared with non-users. Among 1827 healthy twins, Jackson et al also found a significant decrease in alpha diversity and alteration of bacterial composition in PPI users. Notably, both studies found a higher abundance of oral commensals, including Streptococcaceae, among PPI users. These studies controlled for some potential confounders in their analyses; however, intersubject variability could have influenced their results.
Getting Underneath Observed Frailty Transitions: Meaningful Change, Prevention and Intervention.
Bandeen-Roche K, Espinoza SE
J Am Geriatr Soc. 2017 Nov;65(11):2455-2456. doi: 10.1111/jgs.15034. Epub 2017 Sep 5.
We congratulate Lauren Pollack, Thuy-Tien Dam, and their colleagues on their intriguing study of frailty status transitions in older men.1 By describing the natural history of frailty progression—and remission, the authors’ study lays epidemiological groundwork for evaluating public health- and policy-based strategies to improve the health reserve of older adults. The considerably high rate of transitioning observed suggests that such strategies could have substantial public health importance. Because, ideally, frailty transitions indicate changes in physiological reserve and functioning, well characterizing frailty transitions ultimately may also provide an anchor by which to detect these underlying changes and delineate their etiology.
Differential effects of metformin on age related comorbidities in older men with type 2 diabetes.
Wang CP, Lorenzo C, Habib SL, Jo B, Espinoza SE
J Diabetes Complications. 2017 Apr;31(4):679-686. doi: 10.1016/j.jdiacomp.2017.01.013. Epub 2017 Jan 28.
AIMS: To identify distinct temporal likelihoods of age-related comorbidity (ARC) diagnoses: cardiovascular diseases (CVD), cancer, depression, dementia, and frailty-related diseases (FRD) in older men with type 2 diabetes (T2D) but ARC naïve initially, and assess the heterogeneous effects of metformin on ARCs and mortality.
METHODS: We identified a clinical cohort of male veterans in the United States who were ≥65years old with T2D and free from ARCs during 2002-2003. ARC diagnoses during 2004-2012 were analyzed using latent class modeling adjusted for confounders.
RESULTS: The cohort consisted of 41,204 T2D men with age 74.6±5.8years, HbA1c 6.5±0.97%, and 8393 (20.4%) metformin users. Four ARC classes were identified. ‘Healthy Class’ (53.6%): metformin reduced likelihoods of all ARCs (from 0.14% in dementia to 6.1% in CVD). ‘High Cancer Risk Class’ (11.6%): metformin reduced likelihoods of CVD (13.3%), cancer (45.5%), depression (5.0%), and FRD (13.7%). ‘High CVD Risk Class’ (17.4%): metformin reduced likelihoods of CVD (48.6%), cancer (3.2%), depression (2.8%), and FRD (6.3%). ‘High Frailty Risk Class’ (17.2%): metformin reduced likelihoods of CVD (18.8%), cancer (3.9%), dementia (3.8%), depression (15.6%), and FRD (23.8%).
CONCLUSIONS: Metformin slowed ARC development in old men with T2D, and these effects varied by ARC phenotype.
Moving toward ‘common’ use of the marmoset as a non-human primate aging model
Adam B. Salmon
Pathobiol Aging Age Relat Dis. 2016; 6: 10.3402/pba.v6.32758. Published online 2016 Jul 22. doi: 10.3402/pba.v6.32758
Great leaps forward in our understanding of the basic biology of aging, including interventions that extend longevity, have come about from using common laboratory animal models. As we now strive to apply these findings for human benefit, a serious concern arises in how much of this research will directly translate to normal, largely healthy, and genetically varied populations of people. Laboratory animals, including rodents, are only distantly related to humans and have undergone different evolutionary pressures that likely have driven species-specific idiosyncrasies of aging. Due to our long lifespans, any outcomes of longevity interventions in human studies are unlikely to be discovered even during the research careers of current graduate students. There is then strong rationale for testing whether the interventions discovered that slow aging in laboratory rodents, such as dietary restriction, mTOR (mechanistic target of rapamycin)inhibition, or acarbose (1–3), will also extend the lifespan of species more closely related to humans. In this context, the calorie restriction studies utilizing non-human primates and performed by the University of Wisconsin and the National Institute on Aging are prime examples of this approach. However, the rhesus macaques used in these studies also have relatively long lifespans which required time commitment in the order of decades to accomplish the recently published final results (4–6).
Most non-human primates that can be kept in healthy laboratory populations have relatively long lifespans, but the small South American common marmoset (Callithrix jacchus) may offer a number of advantages over other non-human primate species, particularly for researchers interested in aging.