Lifeboat Foundation

Klotho (KL) is described as an anti-aging gene because mutation of Kl gene leads to multiple pre-mature aging phenotypes and shortens lifespan in mice. Growing evidence suggests that an increase in KL expression may be beneficial for age-related diseases such as arteriosclerosis and diabetes. It remains largely unknown, however, how Kl expression could be induced. Here we discovered novel molecular mechanism for induction of Kl expression with a small molecule ‘Compound H’, N-(2-chlorophenyl)-1 H-indole-3-caboxamide. Compound H was originally identified through a high-throughput screening of small molecules for identifying Kl inducers. However, how Compound H induces Kl expression has never been investigated. We found that Compound H increased Kl expression via demethylation in CpG islands of the Kl gene. The demethylation was accomplished by activating demethylases rather than inhibiting methylases. Due to demethylation, Compound H enhanced binding of transcription factors, Pax4 and Kid3, to the promoter of the Kl gene. Pax4 and Kid3 regulated Kl promoter activity positively and negatively, respectively. Thus, our results show that demethylation is an important molecular mechanism that mediates Compound H-induced Kl expression. Further investigation is warranted to determine whether Compound H demethylates the Kl gene in vivo and whether it can serve as a therapeutic agent for repressing or delaying the onset of age-related diseases.

Keywords: klotho, methylation, Pax4, Kid3, CpG island.

Pre-mature aging phenotypes were eminent in the klotho (Kl)-deficient mice, which have ~ 10 copies of a transgene integrated in the 5’ flanking region of the Kl gene disrupting its expression [1]. The klotho mice die around ~ 2 months of age after birth due to multiple aging-related organ failures [1]. Later, the role of KL in aging was confirmed by the reproduction of the same aging phenotypes in Kl knockout homozygous (Kl −/−) mice [2]. On the other hand, overexpression of KL extends lifespan by 20–30% [2, 3]. The protein products of Kl gene can be divided into two forms: membrane-integrated form of Kl and non-integrated form of Kl which includes secreted and soluble Kl (sKl). These two type of proteins are produced from the two transcripts that arise from a single kl gene due to alternative RNA splicing [4, 5].

Systemic gamma-aminobutyric acid (GABA) therapy prevents or ameliorates type 1 diabetes (T1D), by suppressing autoimmune responses and stimulating pancreatic beta cells. In beta cells, it increases insulin secretion, prevents apoptosis, and induces regeneration. It is unclear how GABA mediates these effects. We hypothesized that Klotho is involved. It is a multi-functional protein expressed in the kidneys, brain, pancreatic beta cells, other tissues, and is cell-bound or soluble. Klotho knockout mice display accelerated aging, and in humans Klotho circulating levels decline with age, renal disease and diabetes. Here, we report that GABA markedly increased circulating levels of Klotho in streptozotocin (STZ)-induced diabetes. GABA also increased Klotho in the islet of Langerhans of normal mice, as well as the islets and kidneys of STZ-treated mice. In vitro, GABA stimulated production and secretion of Klotho by human islet cells. Knockdown (KD) of Klotho with siRNA in INS-1E insulinoma cells abrogated the protective effects of GABA against STZ toxicity. Following KD, soluble Klotho reversed the effects of Klotho deficiency. In human islet cells soluble Klotho protected against cell death, and stimulated proliferation and insulin secretion. NF-κB activation triggers beta-cell apoptosis, and both GABA and Klotho suppress this pathway. We found Klotho KD augmented NF-κB p65 expression, and abrogated the ability of GABA to block NF-κB activation. This is the first report that GABAergic stimulation increases Klotho expression. Klotho protected and stimulated beta cells and lack of Klotho (KD) was reversed by soluble Klotho. These findings have important implications for the treatment of T1D.

Circa 2017

Hunting for meat was a critical step in all animal and human evolution. A key brain-trophic element in meat is vitamin B₃ / nicotinamide. The supply of meat and nicotinamide steadily increased from the Cambrian origin of animal predators ratcheting ever larger brains. This culminated in the 3-million-year evolution of Homo sapiens and our overall demographic success. We view human evolution, recent history, and agricultural and demographic transitions in the light of meat and nicotinamide intake. A biochemical and immunological switch is highlighted that affects fertility in the ‘de novo’ tryptophan-to-kynurenine-nicotinamide ‘immune tolerance’ pathway. Longevity relates to nicotinamide adenine dinucleotide consumer pathways. High meat intake correlates with moderate fertility, high intelligence, good health, and longevity with consequent population stability, whereas low meat/high cereal intake (short of starvation) correlates with high fertility, disease, and population booms and busts. Too high a meat intake and fertility falls below replacement levels. Reducing variances in meat consumption might help stabilise population growth and improve human capital.

Keywords: Meat, nicotinamide, evolution, NAD(H), vitamin B₃, Malthus, fertility, immunological tolerance, longevity.

Continue reading “Meat and Nicotinamide: A Causal Role in Human Evolution, History, and Demographics” »

A drug that helps people after organ transplants has extended the lives of fruit flies, worms, and mice. The next step is to see what it will do for our pets.

Two unmanned commercial satellites have docked in orbit for the first time. On February 25, Northrop Grumman’s Mission Extension Vehicle-1 (MEV-1) linked up with the Intelsat 901 (IS-901) communication satellite at an altitude of 22,416 mi (36,076 km) above the Earth as part of a project to extend the service life of satellites that are running low on propellants.

The building and launching of satellites is extremely expensive, so it’s more than just frustrating when a perfectly good spacecraft has to be disposed of or abandoned simply because it has run out of the propellants needed to keep it in its proper orbit and pointed at Earth. There have been a number of solutions proposed for this problem – in this case Northrop’s MEV-1 is designed to match orbits with aging satellites, dock, and take over the job of maintaining orbit and attitude.

Continue reading “Space docking first gives commercial satellites a new lease of life” »

I interviewed Aubrey de Grey from the SENS Research Foundation about the fight to eliminate ageing in humans, why he believes the first 1,500 year old human has probably been born and the transhumanist movement. Trying to grow the channel (on futurism/transhumanism) so please do sub if this is of interest.

I interview biologist Aubrey de Grey, Chief Science Officer of the SENS Research Foundation, about whether humans can overcome ageing (and therefore theoretically live for thousands of years). We discuss the obstacles to ending ageing, whether the first 1,500 year old human is currently alive and the transhumanist movement. Oh and I say longitudinal rather than longevity escape velocity which was a little embarrassing!

Continue reading “Can humans defeat ageing? Aubrey de Grey interview” »

Scientists at the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have made a surprising discovery that could help explain our risk for developing chronic diseases or cancers as we get older, and how our food decomposes over time.

What’s more, their findings, which were reported recently in the Proceedings of the National Academy of Sciences (PNAS), point to an unexpected link between the ozone chemistry in our atmosphere and our cells’ hardwired ability to ward off disease.

“The beauty of nature is that it often decides to use similar chemistries throughout a system, but we never thought that we would find a common link between atmospheric chemistry, and the chemistry of our bodies and food,” said Kevin Wilson, the deputy director of Berkeley Lab’s Chemical Sciences Division who led the study. “Our study is the first to explore another chemical pathway that might affect how well the cells in our bodies — and even our food — can respond to oxidative stress, such as pollution, over time.”

https://youtube.com/watch?v=9-z0kglwpwo

They don’t waste much time getting right into it. He is 57 but has been told he is physically 47.

Dr. Aubrey de Grey of SENS Research Foundation was interviewed by the extremely popular Joe Rogan, and they discussed the damage repair approach to aging. Dr. de Grey talked about the current state of aging research, including stem cell therapies, and explained the role of SENS in developing next-generation rejuvenation biotechnology therapies. He also brought up the role of funding, a key bottleneck in research and development, and gave his prognosis on how quickly these therapies will be developed.

Are American Federal and Supreme Court Justices lifetime appointments? If so, what’s going to happen if radical life extension becomes a reality? :

“Like all Federal judges, Supreme Court Justices serve lifetime appointments on the Court”