Genetic Manipulation to Increase the Proportion of Brown Fat Tissue is Shown to Modestly Extend Mouse Life Span

The operation of metabolism determines species longevity, and in short-lived species this link tends to be highly variable in response to circumstances: exercise, diet, and consequences such as amounts and types of muscle and fat tissue. Longer lived species such as our own are, if anything, remarkable for the comparative lack of variation in life span across large differences in diet and the configuration of muscle and fat in our bodies. As researchers continue to map the interaction of metabolism and aging in laboratory mice, one interesting theme that has emerged is the importance of brown adipose tissue. In the open access paper noted here, the authors report that increasing the proportion of fat tissue that is brown rather than white can produce a 10-15% increase in mouse life span. They suggest this is mediated by SIRT3 activity and downstream effects on mitochondrial function. The results here might be compared with a very intriguing study published last year in which researchers described what happens to metabolism and fat tissue in mice if their sense of smell is disabled. That resulted in healthier, metabolically superior mice characterized by a greater proportion of brown fat tissue. It built upon a range of past research suggesting that sense of smell plays a sizable role in the metabolic reaction to food. Unfortunately, for these and all other similar metabolic manipulations, we can't expect sizable results to transfer to humans and other long-lived mammals. For those interventions wherein researchers can directly compare mice and humans, the outcome on human life spans is much smaller, and supporting evidence strongly suggests that this holds up across the spectrum of everything involving diet, fat, and metabolism. The health benefits - distinct from effects on the pace of aging - may still be worth pursuing, if the costs are reasonable, however. Consider calorie restriction, for example. There is also the point that a 10% life span effect in short-lived species is somewhere in the margin of error, and may well be hard to replicate. Looking back at the past few decades, 10% effects come and go in mice. One of the challenges is that an intervention may make mice choose to eat less for any number of reasons. The effects of calorie restriction are so large that they can swamp whatever else is going on in the study. The researchers here report carefully on the details of their many measures of metabolism, but one always has to read those details in order to understand whether they rule out a calorie restriction effect. That may not be the case here, for all that various aspects of the biochemistry under study match up well with what is presently known. Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14 There are two distinctly different types of fat found in mammals: white adipose tissue (WAT), which is an essential site for triglyceride storage, and brown adipose tissue (BAT). The BAT is a protective mechanism of recent interest. BAT enhances energy metabolism and protects against cold exposure and obesity. A novel model to investigate the role of BAT in healthful aging and lifespan is the mouse model of the gene knockout (KO) of the regulator for G protein signaling 14 (RGS14), which has increased BAT. Most prior work on RGS14 focused on its effects on embryonic development and on the visual cortex and central nervous system. The role of BAT in RGS14 KO and its ability to enhance lifespan and improve metabolism, the focus of the present investigation, have never been explored. To confirm the essential role of BAT in mediating the protection in the RGS14 KO, we transplanted BAT from RGS14 KO to wild type (WT) mice, a technique that is equivalent to a BAT KO, as it disrupts the salutary phenotype in the RGS14 KO and transplants these features to their WT, receiving the BAT. Lifespan was monitored in the mice, and we observed significantly longer lifespan of RGS14 KO vs. WT mice. Median lifespan was increased by 4 months from 24 to 28 months. Median lifespan and maximum lifespan were increased to a similar extent in females and males. The older RGS14 KO mice were also protected from aging-induced atrophy of the thymus. It is also important that BAT protects against the aging phenotype, for example, graying and loss of hair, dermatitis, and hunched back, all of which were observed in old WT mice, but not observed in old RGS14 KO mice or in old WT mice, which received BAT transplants. RGS14 KO mice had improved body composition compared to WT mice. RGS14 KO mice had lower body weight and WAT index (% of white fat to total body weight). The BAT index (% of brown fat to total body weight) was increased in RGS14 KO by 77% compared to their WT littermates. From RT-qPCR analysis to profile changes in BAT transcript levels, we found that BAT-specific markers were significantly upregulated. As healthful longevity and BAT are known to improve metabolic function, we assessed metabolism through indirect calorimetry and demonstrated greater oxygen consumption in RGS14 KO than WT mice. In the RGS14 KO, SIRT1 was downregulated, while SIRT3 was upregulated. To confirm the role of the SIRT3 mechanism, a double KO (RGS14 KO X SIRT3 KO) was studied. The RGS14 X SIRT3 double KO mice lost their improved metabolism, pointing to SIRT3 as a mediator of the beneficial effects on metabolic regulation in the RGS14 KO animals. Therefore, RGS14 deficiency promotes increased SIRT3 activity, not only by increasing its expression levels, but also by increasing the availability of NAD+, an important cofactor required for sirtuin function. SIRT3 activation, in turn, leads to improved mitochondrial biogenesis, providing the molecular basis for healthful aging in the RGS14 KO animals.

https://www.fightaging.org/archives/2018/04/genetic-manipulation-to-increase-the-proportion-of-brown-fat-tissue-is-shown-to-modestly-extend-mouse-life-span/

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Fibrosis is Harmful, and Varied Approaches to Suppress it are Under Development

Fibrosis is one of the major age-related failures of mammalian regenerative processes. Instead of reconstructing or maintaining the correct form of tissue, scar-like structures are deposited, disrupting organ function. Enough of this is fatal in organs such as the heart, liver, kidney, or lungs. Rising levels of fibrosis, and particularly following trauma such as infection or structural failure of aged blood vessels, are a significant component of loss of organ function and mortality in the old. Worse, the medical community has little in the way of therapies that can treat fibrosis; those that do exist are marginal in their benefits. The causes of fibrosis are thought to be complex and tissue specific because regeneration is complex and tissue specific. Considered at the high level, it is a coordinated dance carried out between stem and progenitor cells of various types, the somatic cells already present in the tissue to be worked on, and immune cells, with many and varied signals passing back and forth between all of these types. The lower level details vary considerably by tissue type and structure. In recent years, however, investigation of senescent cells - and the ability to slow aging by targeted removal of those cells - has revealed that a fair amount of fibrosis appears secondary to cellular senescence. Senescent cells generate chronic inflammation, as well as signals related to construction and destruction of the extracellular matrix, so it seems almost obvious in hindsight that they would be involved. A range of supporting evidence makes it seem plausible that inflammation causes disarray in the role of immune cells in regeneration and tissue maintenance, and comparisons between highly regenerative and less regenerative species suggest that immune cells strongly determine the quality of regeneration. Fibrosis in the lungs and other organs can be reversed through the use of senolytic treatments that destroy some fraction of senescent cells, a result so far demonstrated in animal studies only. The research noted here is an example of bypassing all of these consideration in favor of outright sabotage of a crucial mechanism in tissue maintenance that is needed for fibrosis to occur. Unfortunately, this will also sabotage other important forms of normal regeneration, which may well limit its application to the treatment of critical cases after the fact, rather than as a form of prevention to keep the damage of fibrosis to a low level. Other forms of medicine with similar downsides have done well - think of the biologics for autoimmune disease that work through blanket suppression of parts of the immune system, for example - but I would hope that the research community can do better than this class of approach in the years ahead. Blocking Matrix-Forming Protein Might Prevent Heart Failure Researchers tested a manufactured peptide called pUR4 to block the fibronectin protein in human heart cells donated by heart failure patients. The treatment prevented the human heart cells from failing and restored their function. The treatment also reduced fibrosis and improved heart function after a simulated heart attack in mice. Fibronectin is normally a good actor in the body. It helps form a cell-supporting matrix for the body's connective tissues, aiding tissue repair after injury. But after a heart attack, fibronectin overreacts, it polymerizes and helps produce too much connective matrix. It also causes hyperactive production of clogged and dysfunctional cardiac myofibroblast cells that damage the heart. The pUR4 compound is designed so it will attach to surface points on fibronectin, effectively inhibiting its effects in injured heart cells. The pUR4 molecular treatment used in the current study is one of several compounds that show promise in preliminary preclinical research data. A key question in the current study was verifying the results of pUR4 targeted molecular therapy in both the mouse models and human heart failure cells. In mice with simulated heart attack that as a control experiment received a placebo therapy, the animals developed significant fibrosis and heart failure. When researchers treated mice with pUR4 for just the first seven days after heart attack, or genetically deleted fibronectin activity from the heart cells of mice, these reduced fibrosis and improved cardiac function. Treatment of human failing heart cells with pUR4 also reduced their fibrotic behavior. The researchers emphasize it's too early to know whether the experimental therapy in this study can one day be used to treat human heart patients clinically. Extensive additional research is needed first, including proving pUR4's safety in larger animal models and then moving on to establish proof-of-principal effectiveness treating heart failure in those models. Inhibiting Fibronectin Attenuates Fibrosis and Improves Cardiac Function in a Model of Heart Failure Fibronectin (FN) polymerization is necessary for collagen matrix deposition and is a key contributor to increased abundance of cardiac myofibroblasts (MF) following cardiac injury. We hypothesized that interfering with FN polymerization or its genetic ablation in fibroblasts would attenuate MF, fibrosis, and improve cardiac function following ischemia/reperfusion (I/R)-injury. Mouse and human MF were utilized to assess the impact of the FN polymerization inhibitor (pUR4) in attenuating pathologic cellular features such as proliferation, migration, extracellular matrix (ECM) deposition, and associated mechanisms. To evaluate the therapeutic potential of inhibiting FN polymerization in vivo, wild-type (WT) mice received daily intraperitoneal injections of either pUR4 or control peptide immediately after cardiac surgery, for seven consecutive days. pUR4 administration on activated MF reduced FN and collagen deposition into the ECM and attenuated cell proliferation, likely mediated through decreased c-myc signaling. pUR4 also ameliorated fibroblast migration. In vivo, daily administration of pUR4 for seven days post-I/R significantly reduced MF markers and neutrophil infiltration. This treatment regimen also significantly attenuated myocardial dysfunction, pathologic cardiac remodeling, and fibrosis up to 4 weeks post-I/R. Finally, inducible ablation of FN in fibroblasts post-I/R resulted in significant functional cardioprotection with reduced hypertrophy and fibrosis.

https://www.fightaging.org/archives/2018/04/fibrosis-is-harmful-and-varied-approaches-to-suppress-it-are-under-development/

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