James' World 2

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Take a flashlight – the one on your phone will do – turn it on and place the pad of your index finger over the bulb. See that red glow? You might think it’s something to do with blood, but you’d be wrong. It’s photons of red light bouncing around inside your finger, looking for somewhere to land.

This simple experiment is a doorway to one of the most profound and surprising biological discoveries of recent years. “Light is a nutrient,” says Bob Fosbury, who was an astrophysicist at the European Southern Observatory before he turned his attention to the biology of light. That’s obviously true for plants, which use light to make carbohydrates. But it turns out it’s also true for animals and fungi, all of which exploit light in a hitherto unappreciated way. All living organisms – including us – are solar-powered.

Sunlight has long been understood to be critical to life on Earth. But the fact that light is also used to oil the wheels of metabolism is only just, er, coming to light. Long wavelengths, which come from red and infrared (IR) light, are particularly beneficial for creating energy, and are readily available from sources including sunlight and incandescent bulbs.

But changes in lighting intended to help save energy have inadvertently deprived us from this crucial supply. The irony is that just as we have discovered the benefit of red light, we are unintentionally starving ourselves of it.

How modern bulbs starved us of red light

The story begins in the early 2000s with the widespread adoption of two now-ubiquitous energy efficiency technologies. The first was the light-emitting diode (LED), which largely replaced energy-guzzling incandescent bulbs. Although this change helped conserve energy, it had other unforeseen consequences. The second was window glass that filters out IR, designed to prevent heat leaking into or out of buildings. Together, these dramatically narrowed the spectrum of light we are exposed to indoors, an environment where most humans spend up to 90 per cent of their time. “We lost about 95 per cent of the spectrum,” says neuroscientist Glen Jeffery at University College London. “Suddenly, without warning, boom, the long wavelengths go. And that’s a problem.”

For the vast majority of human existence, those long wavelengths of light were unavoidable. Daylight is rich in visible red light, which has wavelengths of about 650 to 750 nanometres. It also emits vast and invisible (to us, at least) quantities of IR, which extends out to about 2500 nanometres.

People who spend much of the day outside are naturally exposed to these long wavelengths, even when fully clothed. When long-wavelength light hits a human body, it sails through clothing and penetrates deep into tissues (short-wavelength light such as UV, in contrast, is absorbed by clothing, which is why covering up helps prevent sunburn). Red and IR are also abundant in moonlight and in the glow of a campfire. Indoor light, too, used to be full of these wavelengths, either from sunlight streaming through windows or light sources such as open fires, candles, and oil and gas lamps. The invention of the electric light didn’t change that, as the spectrum of an incandescent light bulb closely matches that of the sun.

But the adoption of energy-efficient lighting and windows robbed us of longer parts of the spectrum. Glass that filters out IR obviously blocks that portion of sunlight, and while LEDs throw out a lot of visible light, they produce nothing beyond about 750 nm. “LEDs are completely dark in the infrared,” says Fosbury. Scott Zimmerman, founder of the lighting company Silas Inc. in New Jersey who collaborates with Fosbury and Jeffery, calls LED light “ultra-processed”, an analogy with ultra-processed food. The combined effect of ultra-processed light and modern glass means that the average human today receives much less long-wavelength light than their ancestors did.

At the same time, conditions such as obesity, type 2 diabetes, dementia and early-onset cancers are on the march. The usual suspects for this are poor diet and lack of exercise. But according to Fosbury, Jeffery and others, these are only a piece of the puzzle; another reason, perhaps the principal one, is red-light deprivation. “There’s not a single cause, but I do increasingly think that light is the most fundamental and dominant one,” says Fosbury. “And it’s probably the easiest one to solve.”

To understand why light is so vital, we have to go back in time again, to the Soviet Union of the late 1980s, where, at the USSR Academy of Sciences in Moscow, a biophysicist called Tiina Karu was experimenting with red and near-infrared light as a therapy. She discovered that they were useful in wound healing and pain management and wondered what the mechanism was. Eventually she hit on energy metabolism, specifically the pace at which mitochondria inside the body’s cells produce a molecule called ATP. Red light, she found, accelerated this process.

Karu’s work never found a wide audience, mainly because she came from the wrong side of the Iron Curtain, according to Jeffery. But she was right, and today red-light therapy is everywhere, used to promote wound healing and treat skin conditions, hair loss, cognitive impairment, chronic pain, osteoarthritis and much more. The evidence of its efficacy is patchy, but growing, according to John Mitrofanis, a neurologist at the University of Grenoble Alpes in France. There is much debate over the correct doses and wavelengths, but researchers are in agreement that its effects are mediated by mitochondria.

The key to this is the electron transport chain, a complex and highly orchestrated metabolic process that takes in energetic electrons and passes them down a chain of proteins, creating ATP in the process. ATP is biology’s principal energy currency, analogous to cash in an economy. When a cell needs energy to perform a task – say, building new proteins – it uses ATP.

When mitochondria are bathed in red or IR light, the electron transport chain runs a little faster and more ATP is produced – a process Fosbury calls “photometabolism”. The exact mechanism by which ATP production is accelerated remains a point of contention, but what’s certain is that diseased cells are often short of ATP, so a boost can make up the deficit. That, says Jeffery, explains why red-light therapy is beneficial.

It also explains why taking away red light can be harmful. Jeffery points out that all life on Earth evolved in an environment rich in red light and IR, but humans now mostly live in one stripped of those wavelengths. The result is more sluggish ATP production. To add insult to injury, we have also flooded our indoor environment with shorter wavelengths in the form of blue light from screens and LEDs. Blue light inhibits ATP production by slowing down the electron transport chain. Lose, lose.

The effects are insidious. Fosbury likens long-wavelength light to a vitamin and calls the effects of deprivation “21st-century scurvy”, a nod to the disease of vitamin C deficiency that killed and sickened tens of thousands of sailors in the 18th century. Like scurvy, it creeps up on you. “It’s something that accumulates over a period of time,” says Jeffery.

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A debate is brewing in the oil market: Is the Strait of Hormuz way more “open” than we thought?

Common wisdom held that the crucial waterway is effectively closed to oil tanker traffic. Iran has fired on dozens of tankers attempting to transit the strait. Maritime tracking services using a combination of transponder data and satellite imagery have reported a significant decline in the number of vessels trying to navigate the waters. Global oil inventories continue to be depleted.

But US Energy Secretary Chris Wright told a very different story last week: The strait is open, and oil is flowing significantly faster than the market appreciates.

He would know: The US military is right there, patrolling the water, escorting ships in and out of the strait, protecting them from enemy fire. The Navy provides the Department of Energy with detailed information about which vessels are moving through and when.

“In coordination with the US military, the US Department of Energy maintains the best available data related to oil and oil products leaving the Arabian gulf,” a DOE spokesperson said.

It’s not unlike the Trump administration to jawbone oil prices lower. President Donald Trump has repeatedly said the United States controls the Strait of Hormuz and frequently claims that a deal with Iran is imminent. Secretary Wright has said the United States is ensuring plenty of oil is getting where it needs to go.

Ignoring the bluster, Wall Street analysts have largely relied instead on the third-party tracking data they’ve been receiving, along with industry-reported inventory measurements and other data.

But that might be changing. Or, at least, for the first time since the start of the war, some analysts on Wall Street might at least be willing to consider that the administration may be telling the truth about the state of the oil market.

Confusion reigns

Wright asserted that the seven-day average of oil flowing out of the Strait of Hormuz had increased to 9 million barrels per day. Hussain noted that stood in direct opposition to Iran’s claim that the strait was closed – and ship-tracking data that showed it was about half Wright’s number.

“It is becoming increasingly difficult to know how much oil is leaving the Gulf,” said Hamad Hussain, senior climate and commodities economist at Capital Economics. “Contrasting claims by US and Iranian officials are muddying the waters.”

Wall Street analysts – who use ship tracking services like Kpler and Windward Intelligence, among many other data points, to provide estimates about oil flows – have said oil tankers have been getting roughly 4 million barrels of oil out of the Persian Gulf each day.

In addition to the roughly 7 million barrels per day that Middle Eastern countries have rerouted around the strait through pipelines and other methods, about 11 or 12 million barrels have been flowing out, according to the tracking services. That’s significantly lower than the 20 million barrels per day that the region had exported before the Iran war started.

Wright said that on August 8, total oil coming out of the Gulf exceeded that 20-million-barrel mark.

Kpler defended its data, which is powered by its network of 13,000 owned-and-operated receivers across 190 countries that track 350,000 vessels, updating their location every 5 minutes. It also owns a fleet of low-earth-orbit satellites.

“It is not possible to reconcile the disparity between what we see and what he is quoting,” said Matt Smith, director of commodity research at Kpler.

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On the morning of Aug. 5, an anonymous account on X in India posted seemingly sensational news. The commander of Iran’s Islamic Revolutionary Guards Corps had vowed that his country would never give up its nuclear weapon ambitions as long as Israel and the United States possessed those weapons, the account said.

It was not true, and there’s no evidence that the commander made the remark or that Iran has developed nuclear weapons. The claim soon caromed around the internet anyway.

The quotation appeared on Israeli accounts, and then a television channel there posted it, calling it the first public declaration that Iran was working to build a nuclear bomb. That evening, it made its way into remarks that Prime Minister Benjamin Netanyahu delivered at Mount Herzl in Jerusalem, the country’s national cemetery.

In the United States, Mike Waltz, the Trump administration’s ambassador to the United Nations, reposted the quotation, as did Senator Rick Scott of Florida, a Republican. Fox News also reported the claim, as anchors and guests cited it as evidence of Iran’s duplicity.

The quotation, attributed to Brig. Gen. Ahmad Vahidi, was part of a campaign that succeeded in misleading politicians and news organizations around the world, according to a review by The New York Times. The claim’s spread showed how easily viral disinformation can twist the public debate over matters as serious as war and peace.

It is unclear who fabricated the quotation. However, it appeared intended to bolster Mr. Netanyahu’s longstanding claim that Iran is determined to build a nuclear weapon and that war against Iran was necessary.

President Trump, who had tried to justify the war by citing Iran’s nuclear ambitions, has been searching for a way out of it, and the quotation went viral three days after he said he was halting all attacks on Iran to give peace negotiations a chance.

“This quote was clearly crafted to drive a wedge into peace negotiations,” said Darren L. Linvill of the Media Forensics Hub at Clemson University, who tracks how disinformation and propaganda spread on social media.

Iran’s nuclear program has been a source of international concern and diplomacy for three decades, but the country’s officials have maintained that it has a civilian, not a military, focus. The status of Iran’s nuclear development remains unclear.

The spokesman for Iran’s foreign ministry, Esmail Baghaei, criticized the fake post, calling it “an example of the flood of lies against the Islamic republic.” He blamed Israel, but did not cite evidence.

“The allegations of a link to a nuclear bomb are based on the same thing, a lie they have been feeding the international community for 20 years to justify military aggression,” he told reporters on Sunday.

General Vahidi, who took over command of the Revolutionary Guards in March, has issued numerous statements about the war since it started but not about Iran’s nuclear program. Last year, he addressed the topic in an interview with state media after a 12-day conflict with Israel that culminated in American airstrikes. While Iran would “do things it has not done previously” to defend itself, he said, the country’s position on nuclear weapons “has been stated with complete clarity in the past.”

Questions about the origins of the claim were first reported by Ynet, an Israeli news outlet. Since then, new details about how it spread so widely have emerged.

The first known appearance of the quotation — on the Indian account on X — had numerous red flags. The account, which has 175,000 followers, has been criticized by fact-checkers and the government of Pakistan for sharing false and Islamophobic content.

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Funeral ceremonies for Ayatollah Ali Khamenei, Iran’s supreme leader, in Tehran in July. Credit…Arash Khamooshi/Polaris for The New York Times

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Hmmmm … WOW! This is abject immorality! They fought a civil war to keep slavery. 750,000 people died.

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Racial violence is woven throughout the fabric of the history of the United States. In the centuries following the initial colonization of North America, racial and ethnic minorities—especially African American and Indigenous people—have repeatedly been targeted by white people, often as part of organized actions undertaken by white supremacist groups. Violent race riots often devolved into massacres, though in some instances mass death was intended from the outset, as in many of the military massacres of Native Americans. Since the 1900s, there have also been a number of protests and riots led by African Americans in response to police brutality and continued inequality and discrimination. The following is a list of some of the major incidents of racially motivated violence in U.S. history, organized chronologically.

Just a few:

• New York City draft riot (1863)A major four-day eruption of violence in New York City that resulted from deep worker discontent with the inequities of conscription during the American Civil War.

• Fort Pillow massacre (1864)During the American Civil War, Confederate soldiers slaughtered surrendering African American Federal troops stationed at Fort Pillow, Tennessee, on April 12, 1864. While it is impossible to determine how many people were killed in the battle as opposed to the massacre, between 277 and 295 Union troops—the majority of whom were Black—were killed in total.

• Sand Creek massacre (1864)A force of about 675 U.S. troops carried out a surprise attack upon a camp of Cheyenne and Arapaho people in southeastern Colorado Territory. More than 230 Native Americans were massacred, including some 150 women, children, and older adults.

• Memphis massacre (1866)A brutal and unprovoked attack by a white mob on Black residents of Memphis, Tennessee, occurred a little more than a year after the Confederate surrender in the American Civil War. Acting over several days, from May 1 to 3, the mob murdered 46 African Americans (most of whom were Union veterans) and wounded more than 75 others.

• New Orleans massacre (1866)On July 30, 1866, a mob of white men—acting with the compliance and even aid of local civilian authorities and the police—attacked newly freed African Americans in urban New Orleans. The mob murdered 35 Black citizens and wounded more than 100 others who had gathered peacefully to support a political meeting.

• Camp Grant massacre (1871)A vigilante group consisting of a mix of Anglo-Americans, Mexican Americans, and members of the Indigenous Tohono O’odham people carried out a mass murder of more than a hundred members of the Apache people—mostly women, children, and the elderly—on April 30, 1871. The massacre occurred near Winkelman, Arizona, about 70 miles (115 km) north of Tucson, and derives its name from the nearby Camp Grant, an American military post.

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Springfield race riot: Illinois National Guard soldiers standing among the burned-out residences of Black citizens, Springfield, Illinois, 1908.

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One person was killed in a storm-related car crash as Hurricane Lala imposed fierce winds and pouring rain on Hawaii’s Big Island on Saturday, Gov. Josh Green said.

With the worst likely yet to come, Honolulu Fire Chief Sheldon Hao said first responders have responded to 40 reports of damaged roofs and downed trees. More than 84,000 utility customers in the state, most on the Big Island, were without electricity, according to utility tracker PowerOutage.us.

Lala making landfall on the Big Island would mark history, as a hurricane hasn’t done so in 155 years.

“Hurricane Lala is passing just south of Hawaiʻi Island, where winds are peaking and some areas have already received more than 13 inches of rain,” Green said on X. “Conditions are worsening across Maui County, Oʻahu and Kaua‘i tonight.”

Green, speaking in a video update, said he’s started the process that will lead to the declaration of a major disaster. He did not provide further details about the fatality.

Honolulu Mayor Rick Blangiardi said at a news conference that search and rescue crews were working in dire conditions at Oahu’s Lulumahu Falls Trail to find a hiker.

Additionally, Honolulu Ocean Safety Department director Kurt Lager said lifeguards made 59 rescues Saturday. He urged people not to get in the water on Sunday.

“It’s not a day to come to the beach,” he said at the news conference. “It’s not a day to go paddling or surfing.”

In its latest forecast discussion, National Hurricane Center meteorologists said the hurricane is displaying a possible new track, making it “unclear if Lala will actually make a landfall on the Big Island.”

In an update Saturday night, the center said “the eyewall of Lala is nearing South Point,” on the Big Island, with the hurricane’s official position at 35 miles south of South Point.

Lala was headed northwest at 9 mph, it said.

The tropical cyclone is unleashing what could be life-threatening rain on the Big Island as it produces sustained winds of 75 mph, hurricane center director Michael Brennan said in a video update at 11 a.m. local time.

“Some locations have already picked up more than a foot of rain,” he said. “We’re also seeing numerous hurricane-level wind gusts, especially at higher elevations.”

The most inundated part of the island is its windward or eastern side, with higher elevations getting both precipitation and the strongest winds, Brennan said.

Parts of the windward sides of the Big Island and Maui each reported about a foot of rain or slightly more, the hurricane center said in an update.

“Heavy rain continues to spread across the eastern main Hawaiian Islands,” it said.

Though the center’s forecast cone for the hurricane puts it in line with a historic, direct hit on the Big Island, forecasters late Saturday morning said a developing low-pressure trough to the west could cause Lala to brush by to the south.

The tropical cyclone could strengthen in the next few hours, with its most-damaging time frame being the next 6 to 12 hours, Brennan said. But afterward, the impacts of interacting with the Big Island will weaken it significantly, hurricane center forecasters said.

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Forecasters warn of life-threatening flooding, mudslides and damaging winds, with up to 25 inches of rain possible at higher elevations.

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The American ambassador expressed outrage and declared that the United States stood with the Philippines, the oldest U.S. treaty ally in Southeast Asia.

Yet no one expects China to curb its expansionist activities in the region anytime soon. And there are growing doubts among Asian nations over what the United States would be willing to do to deter China, given the enormous distraction and resource drain of the U.S.-Israeli war against Iran.

The United States is running low on critical weapons, including air defense interceptors. Iran’s missile and drone attacks have forced U.S. troops to leave bases in the Middle East and destroyed the sites, an indication of what the Chinese military — which is much more powerful than Iran’s — could do in a conflict in Asia.

In early July, China conducted a rare test firing of a nuclear-capable intercontinental ballistic missile that carried a dummy warhead, sending it into the Pacific Ocean from a nuclear-powered submarine. It is one of the most powerful elements in its arsenal.

While China tests its might, President Trump’s State Department is closing consulates in Japan and Indonesia, according to congressional officials briefed on the decision.

Mr. Trump’s second term “has been a colossal failure for U.S. interests in the Asia region,” Representative Gregory W. Meeks of New York, the top Democrat on the House Foreign Affairs Committee, said in a statement.

“This strategy, if you can call it one, is a gift to China that is undermining U.S. credibility and harming our national security,” he added.

Trump appointees say the administration is not ceding ground in Asia. In a speech in Manila on Aug. 10, Elbridge Colby, the under secretary of defense for policy, said the Trump administration aimed to “maintain a posture of deterrence by denial along the first island chain” — meaning it was willing to commit military resources to dissuade China from invading or attacking islands that include Taiwan and ones in the Philippines and Japan.

But Mr. Colby also said allies needed to spend more on defense and should try to integrate their militaries with that of the United States — and “not vainly and futilely seek to exclude or supplant us.”

Mr. Trump’s global trade war, whose targets have included Southeast Asian nations, has also revealed to allies and partners that the United States can be a commercial antagonist.

The U.S. government has lacked an economic vision for Southeast Asia for years, as Democratic and Republican politicians retreated from a Pacific Rim trade pact that President Barack Obama promoted.

That has left countries in Southeast Asia wondering what happened to the U.S. drive to ensure that it remains a presence that balances against China.

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The Sierra Madre, a Philippine naval ship, in the South China Sea in 2023. Last month, a Chinese Coast Guard vessel began circling the ship and confronted Philippine service members. Credit…Aaron Favila/Associated Press

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Alzheimer’s disease disproportionately affects women—around two thirds of the people who develop it are female. Why that is the case isn’t totally clear. It may be because women tend to live longer than men or perhaps because of social or genetic factors. But emerging research points to another potential risk factor: menopause.

During menopause, the ovaries stop producing mature eggs, and the production of estrogen, a sex hormone critical to female reproductive health, slows. Research hints that this precipitous drop in estrogen may affect how our brains age.

“One of the prevailing hypotheses is that this sharp decline in estrogen may somehow contribute to differences in brain aging,” including the likelihood of developing Alzheimer’s, says Jennifer Bruno, a cognitive neuroscientist at Stanford University.

Now a new study by Bruno and her colleagues that was published in Neurology on Wednesday provides another clue to the possible link between menopause and dementia.

The researchers analyzed two datasets that included a total of 21,462 patient records; for one of the datasets, nearly 3,000 people had donated their brains for science when they died. Overall, patients who took estrogen-only hormone therapy for menopause were less likely to display signs of memory loss or cognitive decline or to be diagnosed with dementia.

In the nearly 3,000 patients who donated their brains to science, the brains of those who took estrogen were less likely to show neurobiological hallmarks of Alzheimer’s disease, such as beta-amyloid plaques or tangles of tau protein. The researchers accounted for confounding factors such as age, race, history of hypertension and other traits, notes Jacob Shaw, a study co-author and psychiatry resident at Massachusetts General Hospital/McLean Hospital. The other dataset also showed a drop in Alzheimer’s-related biomarkers in living patients who took estrogen.

Importantly, the study surfaces an association between estrogen-only hormone therapy and a lower risk of dementia—it doesn’t prove that estrogen-only therapy prevents or treats dementia.

There may be other factors at play, says Hadi Hosseini, a neuroscientist at Stanford University and the study’s senior author. It could be that women who took estrogen-only hormone therapy were healthier overall than those who did not or had better access to health care, or something else could have been involved, he says.

Another limitation is that the research team didn’t have access to information about why each of the patients had been taking estrogen-only therapy. Because it is associated with an increased risk of endometrial cancer, estrogen-only therapy is primarily recommended for menopause treatment in women who have undergone hysterectomies, but the datasets in this study didn’t include hysterectomy records.

Another complication is that some past research suggests that other hormonal therapies, including a combination of the sex hormone progesterone and estrogen, may be associated with a higher risk of dementia. It’s not totally clear why.

More research into the relationship between menopause, estrogen and dementia—including long-term studies that track patients as they age—is needed, the authors say. “It sets the stage for the future randomized controlled trials,” Bruno says.

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Hmmmm … The Trump administration is screwing the USA for Profit!

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Key Points

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Cases of cyclosporiasis were mounting rapidly in Michigan, and state health officials were homing in on a common thread: Many of those who had fallen ill had eaten at Taco Bell.

On July 1, they asked the company for its supply chain records, crucial information in tracing ingredients that may have caused the outbreak.

On July 3, they wrote and asked for the records again.

On July 6, they wrote a third time. 

“With the rapid nature of this outbreak and the number of people affected, we need to ensure we are completing traceback in a timely manner to preserve public health,” Lauren Edwards, an epidemiologist on the state’s rapid response team, said in an email to executives at Yum Brands, which owns Taco Bell. (The New York Times obtained the correspondence under Michigan’s open records law.)

Later that day, Taco Bell provided some records to the state, which by then was working with the federal Food and Drug Administration. The F.D.A. asked for additional records two days later. Finally, on July 13, the agency received all the records it needed to pinpoint lettuce from a Taylor Farms plant in Mexico as a source of the outbreak.

A federal rule that had been scheduled to take effect in January would have required Taco Bell to send those records within 24 hours. But last year, the Trump administration delayed the implementation of that rule until mid 2028, saying companies needed more time to prepare.

Food safety experts say the postponement has hindered the response to the outbreak, the largest cluster in a record number of cyclospora cases in the United States this year.

“Time translates into illnesses and lives,” said Thomas Gremillion, director of food policy at the Consumer Federation of America, who reviewed the emails from Michigan. He added: “We would have had a much better response to this outbreak if they hadn’t delayed that rule.”

Cyclospora, which can cause explosive diarrhea, cramps and other severe symptoms, has been a recognized driver of foodborne illness for nearly 30 years. But this year’s massive toll — totaling more than 24,500 confirmed or suspected cases so far and two deaths — reveals shortcomings in the U.S. food safety system that may leave Americans more vulnerable to future pathogens, public health experts say.

Many point to an erosion of food safety oversight during the Trump administration, stemming in part from its aggressive efforts to roll back regulations and shrink the federal government. Last year, the F.D.A. laid off many of the staff who supported food inspectors’ travel planning and who coordinate with foreign governments on food safety. (An F.D.A. spokesman said on Friday that “travel support staff and staff that coordinated with foreign governments have been reinstated.”) The administration eliminated a committee tasked with studying problems that led to outbreaks. It also cut a program focused on cyclospora tracking.

“So far this administration has made our food less safe, not safer,” said Scott Faber, the senior vice president for government affairs at the Environmental Working Group. “By firing food safety experts, by reducing the number of inspections, by tracking fewer pathogens, and by failing to set up a traceability system that makes sure that we’re able to to clear the shelves quickly.”

Donald Prater, the F.D.A.’s acting deputy commissioner for food, said the agency responded swiftly with the information it had on hand. He added that even if the 24-hour rule had been in effect, it would not have made a major impact on managing this outbreak response.

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Last year, the Food and Drug Administration cut a program that tracked cyclospora outbreaks and delayed a rule that would have required companies to swiftly provide supply chain records in investigations of foodborne disease outbreaks. Credit…Al Drago for The New York Times

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Metformin is one of the most prescribed medicines in the U.S., primarily to treat or prevent type 2 diabetes. But how it works has been something of a mystery. Now researchers have discovered that the substance essentially transforms a person’s gut cells into a sugar sink, resulting in lowered levels of glucose.

Evidence of this mechanism stretches as far back as 1989, when French metabolic researcher Jean Girard and his colleagues published a paper describing how metformin increased the amount of glucose rats absorbed in their intestines. But when research picked up after the drug was finally approved by the U.S. Food and Drug Administration, in 1995, scientists mostly moved toward the theory that metformin reduced the liver’s production of glucose. “It was as if the preexisting science had never existed,” says University of Cambridge metabolism researcher Stephen O’Rahilly, who was not involved in the new study.

Later, radiologists discovered that metformin can cause patients’ guts to “light up like a beacon” during a positron-emission tomography scan, O’Rahilly says. (This version of the test used a tracer molecule that goes to tissues consuming sugar.) Gradually, metabolic scientists began to think this gut absorption of sugar could be important, and they revisited the old research. Not long after, University of Cambridge mitochondrial biologist Judy Hirst found that at very high levels, the drug blocks mitochondria from using oxygen.

For their new study, Northwestern University mitochondrial biologist Navdeep Chandel and his team wanted to figure out how these two ideas fit together: that metformin both causes the gut to absorb more glucose and blocks mitochondria’s oxygen use. Cell respiration, in which cells convert sugars into usable energy, happens inside mitochondria. So Chandel’s group complemented mitochondrial complex I, an enzyme necessary for cell respiration, with a yeast enzyme that isn’t affected by metformin and that they knew could perform some of the same functions in mice’s guts. In those mice, respiration continued as expected, but metformin didn’t reduce blood sugar levels. They concluded that when accumulated at high-enough levels, metformin, by blocking oxygen use, prompts gut cells to switch to a different metabolic pathway that uses much more sugar to produce energy.

This result is counterintuitive, especially considering metformin’s potential connection to antiaging effects. “All these people always say that for longevity, I want to boost my mitochondria,” Chandel says. “If anything, [metformin is] inhibiting mitochondria reversibly, transitively.”

“The broader lesson,” he adds, “is that inhibiting mitochondria may be beneficial when it is done in the right cells, for the right amount of time, without exposing the whole body to the broad toxicity of a mitochondrial inhibitor.” The new work was reported in Nature Metabolism.

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Thomas Fuchs

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