Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice.

Metabolism and aging are tightly connected. Alpha-ketoglutarate is a key metabolite in the tricarboxylic acid (TCA) cycle, and its levels change upon fasting, exercise, and aging. Here, we investigate the effect of alpha-ketoglutarate (delivered in the form of a calcium salt, CaAKG) on healthspan and lifespan in C57BL/6 mice. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically relevant measurements. We find that CaAKG promotes a longer, healthier life associated with a decrease in levels of systemic inflammatory cytokines. We propose that induction of IL-10 by dietary AKG suppresses chronic inflammation, leading to health benefits. By simultaneously reducing frailty and enhancing longevity, AKG, at least in the murine model, results in a compression of morbidity.

MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage.

Aging is accompanied by altered intercellular communication, deregulated metabolic function, and inflammation. Interventions that restore a youthful state delay or reverse these processes, prompting the search for systemic regulators of metabolic and immune homeostasis. Here we identify MANF, a secreted stress-response protein with immune modulatory properties, as an evolutionarily conserved regulator of systemic and in particular liver metabolic homeostasis. We show that MANF levels decline with age in flies, mice and humans, and MANF overexpression extends lifespan in flies. MANF deficient flies exhibit enhanced inflammation and shorter lifespans, and MANF heterozygous mice exhibit inflammatory phenotypes in various tissues, as well as progressive liver damage, fibrosis, and steatosis. We show that immune cell-derived MANF protects against liver inflammation and fibrosis, while hepatocyte-derived MANF prevents hepatosteatosis. Liver rejuvenation by heterochronic parabiosis in mice further depends on MANF, while MANF supplementation ameliorates several hallmarks of liver aging, prevents hepatosteatosis induced by diet, and improves age-related metabolic dysfunction. Our findings identify MANF as a systemic regulator of homeostasis in young animals, suggesting a therapeutic application for MANF in age-related metabolic diseases.

mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance.

The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high regenerative pressure and is often compromised in aged animals. Here, we show that target of rapamycin (TOR) signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling. Although this activation is required for SCs to rapidly proliferate in response to damage, repeated rounds of damage lead to SC loss. Consistently, age-related SC loss in the mouse trachea and in muscle can be prevented by pharmacologic or genetic inhibition, respectively, of mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight an evolutionarily conserved role of TOR signaling in SC function and identify repeated rounds of mTORC1 activation as a driver of age-related SC decline.

The combination of lithium and l-Dopa/Carbidopa reduces MPTP-induced abnormal involuntary movements (AIMs) via calpain-1 inhibition in a mouse model: Relevance for Parkinson׳s disease therapy.

Lithium has recently been suggested to have neuroprotective effects in several models of neurodegenerative disease including Parkinson׳s disease (PD). Levodopa (l-Dopa) replacement therapy remains the most common and effective treatment for PD, although it induces the complication of l-Dopa induced dyskinesia after years of use. Here we examined the potential use of lithium in combination with l-Dopa/Carbidopa for both reducing MPTP-induced abnormal involuntary movements (AIMs) as well as protecting against cell death in MPTP-lesioned mice. Chronic lithium administration (0.127% LiCl in the feed) in the presence of daily l-Dopa/Carbidopa injection for a period of 2 months was sufficient to effectively reduce MPTP-induced AIMs in mice. Mechanistically, lithium was found to suppress MPTP-induced calpain activities in vivo coinciding with down-regulation of calpain-1 but not calpain-2 expression in both the striatum (ST) and the brain stem (BS). Calpain inhibition has previously been associated with increased levels of the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), which is probably mediated by the up-regulation of the transcription factors MEF-2A and 2D. Lithium was found to induce up-regulation of TH expression in the ST and the BS, as well as in N27 rat dopaminergic cells. Further, histone acetyltransferase (HAT) expression was substantially up-regulated by lithium treatment in vitro. These results suggest the potential use of lithium in combination with l-Dopa/Carbidopa not only as a neuroprotectant, but also for reducing AIMs and possibly alleviating potential side-effects associated with the current treatment for PD.

Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis.

Human cervix cancer is caused by high-risk human papillomaviruses encoding E6 and E7 oncoproteins, each of which alter function of distinct targets regulating the cell cycle, apoptosis, and differentiation. Here we determined the molecular contribution of E6 or E7 to neoplastic progression and malignant growth in a transgenic mouse model of cervical carcinogenesis. E7 increased proliferation and centrosome copy number, and produced progression to multifocal microinvasive cervical cancers. E6 elevated centrosome copy number and eliminated detectable p53 protein, but did not produce neoplasia or cancer. E6 plus E7 additionally elevated centrosome copy number and created large, extensively invasive cancers. Centrosome copy number increases and p53 loss likely contributed to malignant growth; however, dysregulated proliferation and differentiation were required for carcinogenic progression.