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Category: genetics

On the 23rd of this month, Dr. David Sinclair did an Ask Me Anything over at the Futurology subreddit in support of the NAD+ Mouse Project on Lifespan.io. There were a range of interesting questions from the community about his work in aging research, particularly the role of NAD+ in aging.

Dr. David A. Sinclair is a Professor in the Department of Genetics at Harvard Medical School and a co-joint Professor in the Department of Physiology and Pharmacology at the University of New South Wales. He is the co-Director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging and a Senior Scholar of the Ellison Medical Foundation. He obtained his Ph.D. in Molecular Genetics at the University of New South Wales, Sydney in 1995. He worked as a postdoctoral researcher at M.I.T. with Dr. Leonard Guarente; there, he co-discovered a cause of aging for yeast as well as the role of Sir2 in epigenetic changes driven by genome instability.

More recently, he has been in the spotlight for his work with NAD+ precursors and their role in aging and has been helping to develop therapies that replace NAD+, which is lost with aging, in order to delay the diseases of old age. Below are a selection of questions and answers from the AMA, and we urge you to head over to Reddit Futurology to check out the other questions that people asked.

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Many mutations accumulate in the esophagus as we age.

Scientists at the MRC Cancer Unit of the Wellcome Sanger Institute and other departments of the University of Cambridge discovered that healthy esophageal tissue accumulates very high numbers of mutations with age, to the point that, by the time middle age is reached, it is likely to contain more cells with a particular mutation than cells without it [1].

Abstract

The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with NOTCH1 and TP53 mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.

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Protein Chrdl1 appears to regulate brain plasticity.

Researchers from the Salk Institute have discovered that a protein called Chrdl1, secreted by astrocytes, is responsible for driving synapse maturation and limiting brain plasticity later in life [1].

Abstract

In the developing brain, immature synapses contain calcium-permeable AMPA glutamate receptors (AMPARs) that are subsequently replaced with GluA2-containing calcium-impermeable AMPARs as synapses stabilize and mature. Here, we show that this essential switch in AMPARs and neuronal synapse maturation is regulated by astrocytes. Using biochemical fractionation of astrocyte-secreted proteins and mass spectrometry, we identified that astrocyte-secreted chordin-like 1 (Chrdl1) is necessary and sufficient to induce mature GluA2-containing synapses to form. This function of Chrdl1 is independent of its role as an antagonist of bone morphogenetic proteins (BMPs). Chrdl1 expression is restricted to cortical astrocytes in vivo, peaking at the time of the AMPAR switch. Chrdl1 knockout (KO) mice display reduced synaptic GluA2 AMPARs, altered kinetics of synaptic events, and enhanced remodeling in an in vivo plasticity assay.

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Cancer is the poster child of age-related diseases, and a recent study sheds light on why the risk of cancer rises dramatically as we age.

Abstract

For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ∼16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data.

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Congratulations to the Forest Organics team and their awesome new site — https://www.myforestorganics.com/

Could deafness be reversed? Scientists re-grow damaged hair cells that have been killed off by age or noise inside the ear…

Researchers from the University of Rochester found that viruses, genetics and even existing drugs could cause little hairs to regrow in the inner ear. These hairs pick up on noises entering the ear.

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Earlier this year, we hosted the Ending Age-Related Diseases 2018 conference at the Cooper Union, New York City. This conference was designed to bring together the best in the aging research and biotech investment worlds and saw a range of industry experts sharing their insights.

Joe Betts Lacroix of Y Combinator and Vium discusses the different ways in which entrepreneurs can focus on overcoming the diseases of aging, namely direct, indirect, and money-first approaches, and the strengths and weakness of each.

Joe was the primary technical founder of hardware/software startup OQO, which entered the Guinness Book of World Records for building the smallest fully featured PC. His experience spans from biotech research to electronics design. Very experienced in invention, prosecution and monetization of intellectual property, he has over 80 patents granted and pending in fields ranging from biophysics and safety systems to antennas, thermal systems, user interfaces, and analog electronics. He has written numerous peer-reviewed publications in fields such as biophysics, genetics, electronics, and robotics. Joe holds a Harvard A.B., an MIT S.M. and a Caltech research fellowship.

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Researchers healed mice with a genetic metabolic disorder that also affects humans by using a new editing tool to target and correct genetic mutations.

Some babies are born with the metabolic disorder phenylketonuria and need a special diet so that the amino acid phenylalanine doesn’t accumulate in the body. Excess phenylalanine delays mental and motor development. If left untreated, the children may develop mental disabilities.

The cause of this metabolic disorder is a mutation in a gene that provides the blueprint for the enzyme phenylalanine hydroxylase (Pah). The enzyme, which is produced by the cells of the liver, metabolizes phenylalanine.

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