Fasting can improve overall health and protect against aging-associated diseases

In a University of California, Irvine-led study, researchers found evidence that fasting affects circadian clocks in the liver and skeletal muscle, causing them to rewire their metabolism, which can ultimately lead to improved health and protection against aging-associated diseases. The study was published recently in Cell Reports.

The circadian clock operates within the body and its organs as intrinsic time-keeping machinery to preserve homeostasis in response to the changing environment. And, while food is known to influence clocks in peripheral tissues, it was unclear, until now, how the lack of food influences clock function and ultimately affects the body.

“We discovered fasting influences the circadian clock and fasting-driven cellular responses, which together work to achieve fasting-specific temporal gene regulation,” said lead author Paolo Sassone-Corsi, Donald Bren Professor of Biological Chemistry at UCI’s School of Medicine. “Skeletal muscle, for example, appears to be twice as responsive to fasting as the liver.”

The research was conducted using mice, which were subjected to 24-hour periods of fasting. While fasting, researchers noted the mice exhibited a reduction in oxygen consumption (VO2), respiratory exchange ratio (RER), and energy expenditure, all of which were completely abolished by refeeding, which parallels results observed in humans.

“The reorganization of gene regulation by fasting could prime the genome to a more permissive state to anticipate upcoming food intake and thereby drive a new rhythmic cycle of gene expression. In other words, fasting is able to essentially reprogram a variety of cellular responses. Therefore, optimal fasting in a timed manner would be strategic to positively affect cellular functions and ultimately benefiting health and protecting against aging-associated diseases.”

This study opens new avenues of investigation that could ultimately lead to the development of nutritional strategies to improve health in humans.

Sassone-Corsi first showed the circadian rhythm-metabolism link some 10 years ago, identifying the metabolic pathwaysthrough which circadian proteins sense energy levels in cells.

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Study reveals communication among organs, tissues regulating body’s energy

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More information: Kenichiro Kinouchi et al. Fasting Imparts a Switch to Alternative Daily Pathways in Liver and Muscle, Cell Reports (2018). DOI: 10.1016/j.celrep.2018.11.077

https://medicalxpress.com/news/2019-01-reveals-fasting-health-aging-associated-diseases.html

Potential therapeutic target for amyotrophic lateral sclerosis found

Research led by stem cell scientists at Harvard University points to a potential new biomarker and drug target for amyotrophic lateral sclerosis (ALS), a neurological disease that is extremely difficult to diagnose and treat. Published in Nature Neuroscience, the study used stem cell models of human motor neurons to reveal the gene STMN2 as a potential therapeutic target, demonstrating the value of this human stem cell model approach in drug discovery.

Diagnosing and treating ALS

Patients with ALS experience the loss of motor neurons and progressive paralysis. Following a long diagnostic journey, they may survive up to five years. Two ALS drugs have been approved by the U.S. Food and Drug Administration (FDA), but they act only to slow the disease.

In addition to a cure—or even a treatment that is effective for more ALS patients—a robust test for ALS is sorely needed. For that to happen, scientists need to find a reliable biomarker of the disease.

TDP-43: a hallmark of ALS

About 10 years ago, scientists found aggregates of a protein called TDP-43 in post-mortem neurons from ALS patients. This protein should have been in the nucleus of those neurons, but instead it was being flushed out, and building up in the cytoplasm.

Clearly, some of the genes at work in the trash-disposal system of neurons (called the proteasome) were interacting with TDP-43 in a way that led to ALS. But which genes are involved, and what they are doing, has not been known.

The gene that encodes for TDP-43 can be mutated to trigger ALS. It is passed on to future generations, who then develop either ALS or, in some cases, frontotemporal dementia (FTD). Since TDP-43 aggregates were discovered in ALS patients, they have been well known as a hallmark of the disease.

What the researchers did

TDP-43 is one of many proteins that binds to RNA, which is responsible for transmitting genetic information and translating it into a concise recipe for a given protein, for example part of a growing neuron.

The researchers set out to identify, for the first time, all the possible types of RNA that are regulated by the TDP-43 protein in the context of human neurons. Until now, studies like this have only been carried out in mice and cancer cell lines.

Then, they looked at what happened to each gene when they manipulated TDP-43.

What they found

The researchers reduced the levels of TDP-43 protein in human stem cell-derived motor neurons. Then, using RNA-sequencing, they analyzed how gene expression changed in these cells.

Among the thousand or so genes that changed when TDP-43 was manipulated, one stood out: Stathmin2 (STMN2), a gene that is important in neural outgrowth and repair. STMN2changed consistently in step with TDP-43.

“Once we had a connection between the TDP-43 and the loss of this other critical gene, STMN2, we could see how a motor neuron might begin to fail in ALS,” said Joseph Klim, postdoctoral fellow in the Harvard Department of Stem Cell and Regenerative Biology (HSCRB).

“With the discovery that our human stem cell model had predicted exactly what was happening in patients, Joe went on to test in this system whether fixing Stathmin2 could rescue the motor neuron degeneration in our dish caused by disturbing TDP-43. In a beautiful series of experiments that I believe provide great hope for patients, he went on to show this was exactly the case: rescuing expression of Stathmin2rescued motor neuron growth,” said Kevin Eggan, Professor of Stem Cell and Regenerative Biology at Harvard.

The culprit

The researchers observed that without TDP-43, STMN2‘s perfectly read protein-making instructions turn into nonsense.

“We discovered that when TDP-43 levels are diminished in the nucleus, a cryptic exon is spliced into STMN2 messenger RNA. That basically deletes its instructions for making functional protein,” explained Klim. “It becomes impossible for STMN2 to create a vital component for repairing or growing motor neuron axons.”

Double- and triple-checking

The next step was to see if their findings reflected the reality of a patient’s biology. They obtained data from RNA sequencing studies that used post-mortem samples from ALS patients. Those rare datasets, compared with controls, echoed the team’s original findings in human stem cell models. The data from ALS-patient spinal cords mapped to the cryptic exon, but data from the controls did not.

Luis Williams of Q-State Biosciences, whose Ph.D. thesis in HSCRB was the first major step in this study, added, “Because we had pluripotent stem cells of human origin, we could make cells in a dish that are relevant to ALS and investigate this very specific problem in the right context: with a human genome and all of the genetic factors that regulate motor neurons.”

Why it matters

“These experiments point towards a clear path for testing whether repairing Stathmin2 in patients can slow or stop their disease,” said Professor Eggan. “The discovery we have made suggests a clear approach for developing a potential therapy for ALS—one that would intervene in all but a very small number of individuals, regardless of the genetic cause of their disease.”

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Ezogabine treatment shown to reduce motor neuron excitability in ALS patients

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More information: Joseph R. Klim et al, ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair, Nature Neuroscience (2019). DOI: 10.1038/s41593-018-0300-4

https://medicalxpress.com/news/2019-01-reveals-potential-therapeutic-amyotrophic-lateral.html

Can Medical Marijuana Help Doctors’ Practices Thrive?

Is Medical Marijuana Right for Your Practice?

Medical marijuana presents a looming decision for some doctors. As more states legalize medical marijuana, should doctors get involved? Will it be beneficial to their medical practice? Or does it entail the type of work and effort that makes it wiser to stay away?

Almost every state lets doctors recommend some form of medical cannabis to their patients, even if it’s only in a very limited program. Some use cannabis as a back-up treatment for a wide variety of conditions and diseases that are hard to treat, including chronic pain, seizures, cancer, and withdrawal from opiate addiction.

What’s more, a growing number of patients are pressing doctors to recommend medical cannabis for them. But so far, most doctors are holding back from joining state programs. In states where physician participation was recently measured, the rate was just 4.1% in Florida,^[1] 2% in New Jersey,^[2] and 1% in New York.^[2]

Whereas 13 states have very limited medical cannabis programs, 33 states have comprehensive ones, and 10 of those have moved on to legalizing pot for recreational use.^[3] More states are expected to follow.

Many doctors who choose to stay away cite these reasons:

1. Cannabis is still seen by many as a drug of abuse. The federal government still classifies it as a dangerous drug that can be addictive and serves as a gateway for stronger drugs. However, many experts dispute this view.

2. Many doctors don’t believe the medical claims. Many possible uses of cannabis still need more research, whereas there is stronger scientific evidence behind some claims, such as treatment for chronic pain and epilepsy.

3. Many fear that some patients just want pot for recreational use. Because recreational marijuana is still illegal in most states, patients might play sick to get marijuana. However, many patients who use medical cannabis have never used it before and are purely interested in its medical effects.

4. Doctors fear prosecution. Cannabis has been illegal at the federal level for almost half a century, but the specter of federal agents prosecuting doctors has never materialized. The possibility of investigations by state licensing boards, on the other hand, still makes many doctors nervous.

Issues to Consider Before Jumping In

Despite these ongoing concerns, the legalization movement for marijuana shows no signs of abating. As public interest in cannabis grows, now is a good time for doctors to consider its medical merits and whether it’s a good idea to add cannabis to their practice.

Doctors who wish to do so face a learning curve. Cannabis for medical use was not taught in medical school, and unless physicians have read the occasional journal article on it, they probably need to take the time to learn more about it.

There are more hurdles. Once physicians educate themselves and enroll in state cannabis programs, they will have to deal with a frankly atypical authorization process—shaped more by legal concerns and politics than by medical traditions, such as the prescription pad and the pharmacy.

To get through these challenges, cannabis doctors have to believe in what they are doing, says Bryan Doner, DO, an emergency physician who runs Compassionate Certification Centers, a chain of cannabis clinics in the western Pennsylvania.

“You need to have some passion to be a medical marijuana physician,” he says. When he founded the company in 2015, “I had some worries about whether this would work. It’s complicated. But my passion and my knowledge helped see me through.”

[MORE]

https://www.medscape.com/viewarticle/907194

Kitov gains on positive preclinical cancer med data

Thinly traded nano cap Kitov Pharma (KTOV +59.6%) is up on a healthy 36x surge in volume in response to encouraging preclinical data on cancer candidate NT219, a novel small molecule cancer drug that fights cancer by activating the “OFF” switch in major oncogenic pathways.

Collaborators at Hebrew University showed that NT219 binds directly to two known modulators of tumor survival, metastasis and drug resistance. The data also showed that short exposure of cancer cells to NT219 triggered irreversible shutdown of these pathways, producing a long-term anti-cancer effect.

https://seekingalpha.com/news/3423113-kitov-60-percent-encouraging-nt219-data

Harvard prof Sinclair behind anti-aging upstart Life Bio, with $50M for research

You can add Life Biosciences to the list of biotech startups looking to make a name for themselves in the burgeoning field of anti-aging drug research.

The Boston-based biotech — which has close ties to David Sinclair, a Harvard geneticist who’s been involved in a variety of startups — says today that it’s lined up $50 million in B round cash. There’s no word on who exactly is investing in the company, but there’s no shortage of ambition.

“We have undertaken a big land-grab of longevity-related intellectual property and we have pulled together a lot of the world’s longevity scientists,” Life CEO Tristan Edwards told the Financial Times in a preview of the announcement. Edwards co-founded the company alongside Sinclair.

The FT notes that the money is coming from wealthy investors attracted to the longevity field, but also offers no specifics. The report adds that the company valuation is set at an estimated $500 million.

Life’s claim to fame is that it’s pursuing what the team describes as “all 8” pathways involved in aging, which includes some familiar targets ranging from cell senescence to stem cell exhaustion and mitochondria dysfunction related to the body’s battery packs. And they’ve established 6 subsidiary units to go after these targets in a collaborative fashion, with Senolytic going after the old cells that accumulate in our bodies as we grow older.

Edwards is a transplant from Australia, which may help explain why Life just days ago invested $7.5 million in Prana Biotechnology $PRAN, a small Melbourne-based outfit that’s been engaged for years in high-risk neurodegeneration work.

Anti-aging research has looped in a variety of players, from Google’s Calico to Unity and Juvenescence. Others in biotech are targeting aging related diseases, like muscle weakness, but going after specific ailments along the path to longevity.

https://endpts.com/harvard-prof-david-sinclair-backs-anti-aging-upstart-life-bio-which-just-raised-50m-for-research/

FDA expands excepted activities as government shutdown drags on

• The partial shutdown of the U.S. government, now into its 24th day, has impacted the Food and Drug Administration, with Commissioner Scott Gottlieb tweeting Sunday that it is “not business as usual” for the agency, which is facing one of the most significant operational challenges in the FDA’s recent history.
• Throughout the shutdown, the FDA has continued activities that address immediate threats to public health. There are, however, additional activities that need to be “considered excepted, unpaid work because they’re necessary to identify and respond to threats to safety of human life,” Gottlieb tweeted.
• After consulting with senior career leaders and public health experts, the FDA determined some of those activities include inspections of high-risk food, drug, medical, device and pharmacy compounding products and facilities — both at home and overseas — as well as food safety and foodborne illness outbreak surveillance, detection and response.

The latest government shutdown, which surpassed the record duration previously held by the 21-day shutdown in 1995-1996 under President Bill Clinton, is showing no sign of ending.

And the FDA is feeling the pressure. The latest Twitter thread from Gottlieb detailed a list of activities that FDA staff will have to carry out unpaid in order to keep food and drugs safe for the American public.

Scott Gottlieb, M.D.

@SGottliebFDA

 · Jan 13, 2019

THREAD – SHUTDOWN UPDATE: The lapse in funding represents one of the most significant operational challenges in FDA’s recent history. But as an agency, we’re committed to fulfilling our consumer protection mandate, to the best of our abilities, under our current configuration.

Scott Gottlieb, M.D.

@SGottliebFDA

We analyzed activities with close input from senior career leaders & public health experts. Our plans always included activities to address immediate threats to human life & safety. But as lapse continues we’re evaluating additional activities we need to except to prevent threats

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1:39 PM – Jan 13, 2019

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Gottlieb identified surveillance sampling of imported high-risk foods, drugs, and devices as another excepted, unpaid task the FDA needs to do. Expanding activities related to surveillance and response for recalls was also on the commissioner’s list.

“Many key functions aren’t getting done,” Gottlieb tweeted. “But we’re focused on maintaining core activities that directly impact consumer safety and save lives. My priority is to our consumer protection mission and the people executing mission critical functions.”

Last week, the FDA warned that Prescription Drug User Fee Act funding is going to run dry in about a month, as the agency cannot accept 2019 user fees during the shutdown.

Drug approval programs for medical devices and generic drugs have between one and three months of funding left. The funding constraints could lead to delayed drug approvals — a potentially risky situation for smaller pharma and biotech companies who will be relying on projected income of new therapies.

https://www.biopharmadive.com/news/fda-shutdown-update-gottlieb-twitter-excepted-work/545954/

Louisiana launching ‘Netflix model’ in Medicaid for hep C drugs

• The Louisiana Department of Health is seeking a drug manufacturing partner for unrestricted access to curative hepatitis C treatments for Medicaid and incarcerated patients. Rather than pay the partner by prescription, the state would agree to pay a subscription fee similar to the Netflix model of paying a fixed monthly cost rather than paying per movie.
• The state said the plan is an attempt to help end the hep C epidemic in Louisiana. At least 39,000 people in the state’s Medicaid program or in its prisons have the disease, which the health department said kills more people than all other infectious diseases combined.
• However, fewer than 3% of Medicaid patients in Louisiana with hep C were treated last year. State officials blamed the lack of treatment on high drug prices.

The state’s effort is a way to confront a health crisis and control costs. Rebekah Gee, secretary of the Louisiana Department of Health, said in a statement the subscription model will “put a cure within reach for our most vulnerable populations while keeping healthcare costs stable.”

A recent HHS Office of the Actuary report on Medicaid projected the program’s expenditures will grow at an average annual rate of 5.7% over the next decade. That’s faster than the gross domestic product.

Hep C treatments have come under scrutiny recently for high price tags. In response, Gilead Sciences said in September it would sell authorized generics of its blockbuster drugs Harvoni and Epclusa through a subsidiary at an annual list price of $24,000 for the most common therapy. As of late, multiple drugmakers have faced vitriol from lawmakers and President Donald Trump for high list prices.

Meanwhile, states across the country are trying to finds ways to bend Medicaid’s cost curve. Some have implemented work requirements for eligibility. A more common policy is Medicaid managed care. Almost a quarter of Americans are covered by Medicaid and a large number of them are on a managed care plan run by a private insurer.

Nearly all of Louisiana Medicaid recipients receive coverage through a managed care company. The thinking goes that the company handles the day-to-day coverage, which makes Medicaid costs more stable for states.

This new model is another way to potentially control costs. Other Medicaid programs will likely follow this initiative closely to see whether it’s worth replicating.

The partnership will allow enrollees unlimited access to antiviral treatments for five years. The plan will cap state spending on hep C drugs and seeks to “treat as many infected people as possible,” Louisiana Gov. John Bel Edwards said in a statement.

Edwards said the current cost of hep C drugs is too high. The new model will allow the state to improve access to therapy while offering a fixed revenue stream for a pharmaceutical partner.

The department of health hopes to treat more than 10,000 Medicaid enrollees and incarcerated people by the end of 2020 through the new model. Officials are aiming to begin the partnership in July.

Supporters of the new model celebrated the announcement on Twitter.

David Mitchell@DavidP4AD

Wow! “Netflix” model to buy Hep-C drugs in LA.
“Announcement came with a solicitation for drug companies to submit bids for the contract.”
This is direct govt negotiation w/drug companies, full access & budget caps. Sounds like promised land to me https://www.washingtonpost.com/health/2019/01/10/louisiana-adopts-netflix-model-pay-hepatitis-c-drugs/?utm_term=.e5f8e6d42446 …

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7:14 AM – Jan 11, 2019

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https://www.biopharmadive.com/news/louisiana-launching-netflix-model-in-medicaid-for-hep-c-drugs/545969/