The science of slowing down aging - even if you're not a tech billionaire
Earlier this year, Harvard scientists reported that they used an anti-aging therapy to reverse blindness in elderly mice. Several other studies in the past decade have suggested that the aging process can be modified, at least in lab organisms. Considering mice and humans share virtually the same genetic makeup, what does the rodent-based study mean for the humans?
In truth, we don’t know. Maybe nothing.
What we do know, however, is that a growing number of people are dedicating themselves to defying the aging process, to turning back the clock – the biological clock, that is. Take Bryan Johnson, a man who is less mouse than human guinea pig. A very wealthy guinea pig.
The 45-year-old venture capitalist spends over $2 million per year reversing his biological clock. To do this, he employs a team of 30 medical doctors and other scientists. His goal is to eventually reset his biological clock to age 18, and “have all of his major organs — including his brain, liver, kidneys, teeth, skin, hair, penis and rectum — functioning as they were in his late teens,” according to a story earlier this year in the New York Post.
But his daily routine paints a picture that is far from appealing: for example, rigorously adhering to a sleep schedule of 8 p.m. to 5 a.m. and consuming more than 100 pills and precisely 1,977 calories daily. Considering all of Johnson’s sacrifices, one discovers a paradox:
To live forever, he must die a little every day until he reaches his goal - if he ever reaches his goal.
Less extreme examples seem more helpful for people interested in happy, healthy aging. Enter Chris Mirabile, a New Yorker who says on his website, SlowMyAge.com, that he successfully reversed his biological age by 13.6 years, from the chronological age of 37.2 to a biological age of 23.6. To put this achievement in perspective, Johnson, to date, has reversed his biological clock by 2.5 years.
Mirabile's habits and overall quest to turn back the clock trace back to a harrowing experience at age 16 during a school trip to Manhattan, when he woke up on the floor with his shirt soaked in blood.
Mirabile, who is now 38, supports his claim with blood tests that purport to measure biological age by assessing changes to a person’s epigenome, or the chemical marks that affect how genes are expressed. Mirabile’s tests have been run and verified independently by the same scientific lab that analyzes Johnson’s. (In an email to Leaps.org, the lab, TruDiagnostic, confirmed Mirabile’s claims about his test results.)
There is considerable uncertainty among scientists about the extent to which these tests can accurately measure biological age in individuals. Even so, Mirabile’s results are intriguing. They could reflect his smart lifestyle for healthy aging.
His habits and overall quest to turn back the clock trace back to a harrowing experience at age 16 during a school trip to Manhattan, when Mirabile woke up on the floor with his shirt soaked in blood. He’d severed his tongue after a seizure. He later learned it was caused by a tumor the size of a golf ball. As a result, “I found myself contemplating my life, what I had yet to experience, and mortality – a theme that stuck with me during my year of recovery and beyond,” Mirabile told me.
For the next 15 years, he researched health and biology, integrating his learnings into his lifestyle. Then, in his early 30s, he came across an article in the journal Cell, "The Hallmarks of Aging," that outlined nine mechanisms of the body that define the aging process. Although the paper says there are no known interventions to delay some of these mechanisms, others, such as inflammation, struck Mirabile as actionable. Reading the paper was his “moment of epiphany” when it came to the areas where he could assert control to maximize his longevity.
He also wanted “to create a resource that my family, friends, and community could benefit from in the short term,” he said. He turned this knowledge base into a company called NOVOS dedicated to extending lifespan.
His longevity advice is more accessible than Johnson’s multi-million dollar approach, as Mirabile spends a fraction of that amount. Mirabile takes one epigenetic test per year and has a gym membership at $45 per month. Unlike Johnson, who takes 100 pills per day, Mirabile takes 10, costing another $45 monthly, including a B-complex, fish oil, Vitamins D3 and K2, and two different multivitamin supplements.
Mirabile’s methods may be easier to apply in other ways as well, since they include activities that many people enjoy anyway. He’s passionate about outdoor activities, travels frequently, and has loving relationships with friends and family, including his girlfriend and collie.
Here are a few of daily routines that could, he thinks, contribute to his impressively young bio age:
After waking at 7:45 am, he immediately drinks 16 ounces of water, with 1/4 teaspoon of sodium and potassium to replenish electrolytes. He takes his morning vitamins, brushes and flosses his teeth, puts on a facial moisturizing sunblock and goes for a brisk, two-mile walk in the sun. At 8:30 am on Mondays, Wednesdays, and Fridays he lift weights, focusing on strength and power, especially in large muscle groups.
Tuesdays, Thursdays and Saturdays are intense cardio days. He runs 5-7 miles or bicycles for 60 minutes first thing in the morning at a brisk pace, listening to podcasts. Sunday morning cardio is more leisurely.
After working out each day, he’s back home at 9:20 am, where he makes black coffee, showers, then applies serum and moisturizing sunblock to his face. He works for about three hours on his laptop, then has a protein shake and fruit.
Mirabile is a dedicated intermittent faster, with a six hour eating window in between 18 hours fasts. At 3 pm, he has lunch. The Mediterranean lineup often features salmon, sardines, olive oil, pink Himalayan salt plus potassium salt for balance, and lots of dried herbs and spices. He almost always finishes with 1/3 to 1/2 bar of dark chocolate.
If you are what you eat, Mirabile is made of mostly plants and lean meats. He follows a Mediterranean diet full of vegetables, fruits, fatty fish and other meats full of protein and unsaturated fats. “These may cost more than a meal at an American fast-food joint, but then again, not by much,” he said. Each day, he spends $25 on all his meals combined.
At 6 pm, he takes the dog out for a two-mile walk, taking calls for work or from family members along the way. At 7 pm, he dines with his girlfriend. Like lunch, this meal is heavy on widely available ingredients, including fish, fresh garlic, and fermented food like kimchi. Mirabile finishes this meal with sweets, like coconut milk yogurt with cinnamon and clove, some stevia, a mix of fresh berries and cacao nibs.
If Mirabile's epigenetic tests are accurate, his young biological age could be thanks to his healthy lifestyle, or it could come from a stroke of luck if he inherited genes that protect against aging.
At 8 pm, he wraps up work duties and watches shows with his girlfriend, applies serum and moisturizer yet again, and then meditates with the lights off. This wind-down, he said, improves his sleep quality. Wearing a sleep mask and earplugs, he’s asleep by about 10:30.
“I’ve achieved stellar health outcomes, even after having had the physiological stressors of a brain tumor, without spending a fortune,” Mirabile said. “In fact, even during times when I wasn’t making much money as a startup founder with few savings, I still managed to live a very healthy, pro-longevity lifestyle on a modest budget.”
Mirabile said living a cleaner, healthier existence is a reality that many readers can achieve. It’s certainly true that many people live in food deserts and have limited time for exercise or no access to gyms, but James R. Doty, a clinical professor of neurosurgery at Stanford, thinks many can take more action to stack the odds that they’ll “be happy and live longer.” Many of his recommendations echo aspects of Mirabile’s lifestyle.
Each night, Doty said, it’s vital to get anywhere between 6-8 hours of good quality sleep. Those who sleep less than 6 hours per night are at an increased risk of developing a whole host of medical problems, including high blood pressure, type 2 diabetes, and stroke.
In addition, it’s critical to follow Mirabile’s prescription of exercise for about one hour each day, and intensity levels matter. Doty noted that, in 2017, researchers at Brigham Young University found that people who ran at a fast pace for 30-40 minutes five days per week were, on average, biologically younger by nine years, compared to those who subscribed to more moderate exercise programs, as well as those who rarely exercised.
When it comes to nutrition, one should consider fasting for 16 hours per day, Doty said. This is known as the 16/8 method, where one’s daily calories are consumed within an eight hour window, fasting for the remaining 16 hours, just like Mirabile. Intermittent fasting is associated with cellular repair and less inflammation, though it’s not for everyone, Doty added. Consult with a medical professional before trying a fasting regimen.
Finally, Doty advised to “avoid anger, avoid stress.” Easier said than done, but not impossible. “Between stimulus and response, there is a pause and within that pause lies your freedom,” Doty said. Mirabile’s daily meditation ritual could be key to lower stress for healthy aging. Research has linked regular, long-term meditation to having a lower epigenetic age, compared to control groups.
Many other factors could apply. Having a life purpose, as Mirabile does with his company, has also been associated with healthy aging and lower epigenetic age. Of course, Mirabile is just one person, so it’s hard to know how his experience will apply to others. If his tests are accurate, his young biological age could be thanks to his healthy lifestyle, or it could come from a stroke of luck if he inherited genes that protect against aging. Clearly, though, any such genes did not protect him from cancer at an early age.
The third and perhaps most likely explanation: Mirabile’s very young biological age results from a combination of these factors. Some research shows that genetics account for only 25 percent of longevity. That means environmental factors could be driving the other 75 percent, such as where you live, frequency of exercise, quality of nutrition and social support.
The middle-aged – even Brian Johnson – probably can’t ever be 18 again. But more modest goals are reasonable for many. Control what you can for a longer, healthier life.
Scientists redesign bacteria to tackle the antibiotic resistance crisis
In 1945, almost two decades after Alexander Fleming discovered penicillin, he warned that as antibiotics use grows, they may lose their efficiency. He was prescient—the first case of penicillin resistance was reported two years later. Back then, not many people paid attention to Fleming’s warning. After all, the “golden era” of the antibiotics age had just began. By the 1950s, three new antibiotics derived from soil bacteria — streptomycin, chloramphenicol, and tetracycline — could cure infectious diseases like tuberculosis, cholera, meningitis and typhoid fever, among others.
Today, these antibiotics and many of their successors developed through the 1980s are gradually losing their effectiveness. The extensive overuse and misuse of antibiotics led to the rise of drug resistance. The livestock sector buys around 80 percent of all antibiotics sold in the U.S. every year. Farmers feed cows and chickens low doses of antibiotics to prevent infections and fatten up the animals, which eventually causes resistant bacterial strains to evolve. If manure from cattle is used on fields, the soil and vegetables can get contaminated with antibiotic-resistant bacteria. Another major factor is doctors overprescribing antibiotics to humans, particularly in low-income countries. Between 2000 to 2018, the global rates of human antibiotic consumption shot up by 46 percent.
In recent years, researchers have been exploring a promising avenue: the use of synthetic biology to engineer new bacteria that may work better than antibiotics. The need continues to grow, as a Lancetstudy linked antibiotic resistance to over 1.27 million deaths worldwide in 2019, surpassing HIV/AIDS and malaria. The western sub-Saharan Africa region had the highest death rate (27.3 people per 100,000).
Researchers warn that if nothing changes, by 2050, antibiotic resistance could kill 10 million people annually.
To make it worse, our remedy pipelines are drying up. Out of the 18 biggest pharmaceutical companies, 15 abandoned antibiotic development by 2013. According to the AMR Action Fund, venture capital has remained indifferent towards biotech start-ups developing new antibiotics. In 2019, at least two antibiotic start-ups filed for bankruptcy. As of December 2020, there were 43 new antibiotics in clinical development. But because they are based on previously known molecules, scientists say they are inadequate for treating multidrug-resistant bacteria. Researchers warn that if nothing changes, by 2050, antibiotic resistance could kill 10 million people annually.
The rise of synthetic biology
To circumvent this dire future, scientists have been working on alternative solutions using synthetic biology tools, meaning genetically modifying good bacteria to fight the bad ones.
From the time life evolved on earth around 3.8 billion years ago, bacteria have engaged in biological warfare. They constantly strategize new methods to combat each other by synthesizing toxic proteins that kill competition.
For example, Escherichia coli produces bacteriocins or toxins to kill other strains of E.coli that attempt to colonize the same habitat. Microbes like E.coli (which are not all pathogenic) are also naturally present in the human microbiome. The human microbiome harbors up to 100 trillion symbiotic microbial cells. The majority of them are beneficial organisms residing in the gut at different compositions.
The chemicals that these “good bacteria” produce do not pose any health risks to us, but can be toxic to other bacteria, particularly to human pathogens. For the last three decades, scientists have been manipulating bacteria’s biological warfare tactics to our collective advantage.
In the late 1990s, researchers drew inspiration from electrical and computing engineering principles that involve constructing digital circuits to control devices. In certain ways, every cell in living organisms works like a tiny computer. The cell receives messages in the form of biochemical molecules that cling on to its surface. Those messages get processed within the cells through a series of complex molecular interactions.
Synthetic biologists can harness these living cells’ information processing skills and use them to construct genetic circuits that perform specific instructions—for example, secrete a toxin that kills pathogenic bacteria. “Any synthetic genetic circuit is merely a piece of information that hangs around in the bacteria’s cytoplasm,” explains José Rubén Morones-Ramírez, a professor at the Autonomous University of Nuevo León, Mexico. Then the ribosome, which synthesizes proteins in the cell, processes that new information, making the compounds scientists want bacteria to make. “The genetic circuit remains separated from the living cell’s DNA,” Morones-Ramírez explains. When the engineered bacteria replicates, the genetic circuit doesn’t become part of its genome.
Highly intelligent by bacterial standards, some multidrug resistant V. cholerae strains can also “collaborate” with other intestinal bacterial species to gain advantage and take hold of the gut.
In 2000, Boston-based researchers constructed an E.coli with a genetic switch that toggled between turning genes on and off two. Later, they built some safety checks into their bacteria. “To prevent unintentional or deleterious consequences, in 2009, we built a safety switch in the engineered bacteria’s genetic circuit that gets triggered after it gets exposed to a pathogen," says James Collins, a professor of biological engineering at MIT and faculty member at Harvard University’s Wyss Institute. “After getting rid of the pathogen, the engineered bacteria is designed to switch off and leave the patient's body.”
Overuse and misuse of antibiotics causes resistant strains to evolve
Seek and destroy
As the field of synthetic biology developed, scientists began using engineered bacteria to tackle superbugs. They first focused on Vibrio cholerae, whichin the 19th and 20th century caused cholera pandemics in India, China, the Middle East, Europe, and Americas. Like many other bacteria, V. cholerae communicate with each other via quorum sensing, a process in which the microorganisms release different signaling molecules, to convey messages to its brethren. Highly intelligent by bacterial standards, some multidrug resistant V. choleraestrains can also “collaborate” with other intestinal bacterial species to gain advantage and take hold of the gut. When untreated, cholera has a mortality rate of 25 to 50 percent and outbreaks frequently occur in developing countries, especially during floods and droughts.
Sometimes, however, V. cholerae makes mistakes. In 2008, researchers at Cornell University observed that when quorum sensing V. cholerae accidentally released high concentrations of a signaling molecule called CAI-1, it had a counterproductive effect—the pathogen couldn’t colonize the gut.
So the group, led byJohn March, professor of biological and environmental engineering, developed a novel strategy to combat V. cholerae. They genetically engineered E.coli toeavesdrop on V. cholerae communication networks and equipped it with the ability to release the CAI-1 molecules. That interfered with V. cholerae progress.Two years later, the Cornell team showed that V. cholerae-infected mice treated with engineered E.coli had a 92 percent survival rate.
These findings inspired researchers to sic the good bacteria present in foods like yogurt and kimchi onto the drug-resistant ones.
Three years later in 2011, Singapore-based scientists engineered E.coli to detect and destroy Pseudomonas aeruginosa, an oftendrug-resistant pathogen that causes pneumonia, urinary tract infections, and sepsis. Once the genetically engineered E.coli found its target through its quorum sensing molecules, it then released a peptide, that could eradicate 99 percent of P. aeruginosa cells in a test-tube experiment. The team outlined their work in a Molecular Systems Biology study.
“At the time, we knew that we were entering new, uncharted territory,” says lead author Matthew Chang, an associate professor and synthetic biologist at the National University of Singapore and lead author of the study. “To date, we are still in the process of trying to understand how long these microbes stay in our bodies and how they might continue to evolve.”
More teams followed the same path. In a 2013 study, MIT researchers also genetically engineered E.coli to detect P. aeruginosa via the pathogen’s quorum-sensing molecules. It then destroyed the pathogen by secreting a lab-made toxin.
Probiotics that fight
A year later in 2014, a Nature study found that the abundance of Ruminococcus obeum, a probiotic bacteria naturally occurring in the human microbiome, interrupts and reduces V.cholerae’s colonization— by detecting the pathogen’s quorum sensing molecules. The natural accumulation of R. obeumin Bangladeshi adults helped them recover from cholera despite living in an area with frequent outbreaks.
The findings from 2008 to 2014 inspired Collins and his team to delve into how good bacteria present in foods like yogurt and kimchi can attack drug-resistant bacteria. In 2018, Collins and his team developed the engineered probiotic strategy. They tweaked a commonly found bacteria in yogurt called Lactococcus lactis.
Engineered bacteria can be trained to target pathogens when they are at their most vulnerable metabolic stage in the human gut. --José Rubén Morones-Ramírez.
More scientists followed with more experiments. So far, researchers have engineered various probiotic organisms to fight pathogenic bacteria like Staphylococcus aureus (leading cause of skin, tissue, bone, joint and blood infections) and Clostridium perfringens (which causes watery diarrhea) in test-tube and animal experiments. In 2020, Russian scientists engineered a probiotic called Pichia pastoris to produce an enzyme called lysostaphin that eradicated S. aureus in vitro. Another 2020 study from China used an engineered probiotic bacteria Lactobacilli casei as a vaccine to prevent C. perfringens infection in rabbits.
In a study last year, Ramírez’s group at the Autonomous University of Nuevo León, engineered E. coli to detect quorum-sensing molecules from Methicillin-resistant Staphylococcus aureus or MRSA, a notorious superbug. The E. coli then releases a bacteriocin that kills MRSA. “An antibiotic is just a molecule that is not intelligent,” says Ramírez. “On the other hand, engineered bacteria can be trained to target pathogens when they are at their most vulnerable metabolic stage in the human gut.”
Collins and Timothy Lu, an associate professor of biological engineering at MIT, found that engineered E. coli can help treat other conditions—such as phenylketonuria, a rare metabolic disorder, that causes the build-up of an amino acid phenylalanine. Their start-up Synlogic aims to commercialize the technology, and has completed a phase 2 clinical trial.
Circumventing the challenges
The bacteria-engineering technique is not without pitfalls. One major challenge is that beneficial gut bacteria produce their own quorum-sensing molecules that can be similar to those that pathogens secrete. If an engineered bacteria’s biosensor is not specific enough, it will be ineffective.
Another concern is whether engineered bacteria might mutate after entering the gut. “As with any technology, there are risks where bad actors could have the capability to engineer a microbe to act quite nastily,” says Collins of MIT. But Collins and Ramírez both insist that the chances of the engineered bacteria mutating on its own are virtually non-existent. “It is extremely unlikely for the engineered bacteria to mutate,” Ramírez says. “Coaxing a living cell to do anything on command is immensely challenging. Usually, the greater risk is that the engineered bacteria entirely lose its functionality.”
However, the biggest challenge is bringing the curative bacteria to consumers. Pharmaceutical companies aren’t interested in antibiotics or their alternatives because it’s less profitable than developing new medicines for non-infectious diseases. Unlike the more chronic conditions like diabetes or cancer that require long-term medications, infectious diseases are usually treated much quicker. Running clinical trials are expensive and antibiotic-alternatives aren’t lucrative enough.
“Unfortunately, new medications for antibiotic resistant infections have been pushed to the bottom of the field,” says Lu of MIT. “It's not because the technology does not work. This is more of a market issue. Because clinical trials cost hundreds of millions of dollars, the only solution is that governments will need to fund them.” Lu stresses that societies must lobby to change how the modern healthcare industry works. “The whole world needs better treatments for antibiotic resistance.”
Meet Dr. Renee Wegrzyn, the first Director of President Biden's new health agency, ARPA-H
In today’s podcast episode, I talk with Renee Wegrzyn, appointed by President Biden as the first director of a health agency created last year, the Advanced Research Projects Agency for Health, or ARPA-H. It’s inspired by DARPA, the agency that develops innovations for the Defense department and has been credited with hatching world-changing technologies such as ARPANET, which became the internet.
Time will tell if ARPA-H will lead to similar achievements in the realm of health. That’s what President Biden and Congress expect in return for funding ARPA-H at 2.5 billion dollars over three years.
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How will the agency figure out which projects to take on, especially with so many patient advocates for different diseases demanding moonshot funding for rapid progress?
I talked with Dr. Wegrzyn about the opportunities and challenges, what lessons ARPA-H is borrowing from Operation Warp Speed, how she decided on the first ARPA-H project that was announced recently, why a separate agency was needed instead of reforming HHS and the National Institutes of Health to be better at innovation, and how ARPA-H will make progress on disease prevention in addition to treatments for cancer, Alzheimer’s and diabetes, among many other health priorities.
Dr. Wegrzyn’s resume leaves no doubt of her suitability for this role. She was a program manager at DARPA where she focused on applying gene editing and synthetic biology to the goal of improving biosecurity. For her work there, she received the Superior Public Service Medal and, in case that wasn’t enough ARPA experience, she also worked at another ARPA that leads advanced projects in intelligence, called I-ARPA. Before that, she ran technical teams in the private sector working on gene therapies and disease diagnostics, among other areas. She has been a vice president of business development at Gingko Bioworks and headed innovation at Concentric by Gingko. Her training and education includes a PhD and undergraduate degree in applied biology from the Georgia Institute of Technology and she did her postdoc as an Alexander von Humboldt Fellow in Heidelberg, Germany.
Dr. Wegrzyn told me that she’s “in the hot seat.” The pressure is on for ARPA-H especially after the need and potential for health innovation was spot lit by the pandemic and the unprecedented speed of vaccine development. We'll soon find out if ARPA-H can produce gamechangers in health that are equivalent to DARPA’s creation of the internet.
ARPA-H - https://arpa-h.gov/
Dr. Wegrzyn profile - https://arpa-h.gov/people/renee-wegrzyn/
Dr. Wegrzyn Twitter - https://twitter.com/rwegrzyn?lang=en
President Biden Announces Dr. Wegrzyn's appointment - https://www.whitehouse.gov/briefing-room/statement...
Leaps.org coverage of ARPA-H - https://leaps.org/arpa/
ARPA-H program for joints to heal themselves - https://arpa-h.gov/news/nitro/ -
ARPA-H virtual talent search - https://arpa-h.gov/news/aco-talent-search/
Dr. Renee Wegrzyn was appointed director of ARPA-H last October.
Matt Fuchs is the editor-in-chief of Leaps.org and Making Sense of Science. He is also a contributing reporter to the Washington Post and has written for the New York Times, Time Magazine, WIRED and the Washington Post Magazine, among other outlets. Follow him @fuchswriter.