With the population of older people projected to grow dramatically, and the cost of healthcare with it, the future welfare of the country may depend on solving aging, writes philosopher Ingemar Patrick Linden.
It is widely acknowledged that even a small advance in anti-aging science could yield benefits in terms of healthy years that the traditional paradigm of targeting specific diseases is not likely to produce. A more youthful population would also be less vulnerable to epidemics. Approximately 93 percent of all COVID-19 deaths reported in the U.S. occurred among those aged 50 or older. The potential economic benefits would be tremendous. A more youthful population would consume less medical resources and be able to work longer. A recent study published in Nature estimates that a slowdown in aging that increases life expectancy by one year would save $38 trillion per year for the U.S. alone.
A societal effort to understand, slow down, arrest or even reverse aging of at least the size of our response to COVID-19 would therefore be a rational commitment. In fact, given that America’s older population is projected to grow dramatically, and the cost of healthcare with it, it is not an overstatement to say that the future welfare of the country may depend on solving aging.
This year, the kingdom of Saudi Arabia has announced that it will spend up to 1 billion dollars per year on science with the potential to slow down the aging process. We have also seen important investments from billionaires like Google co-founder Larry Page, Amazon founder Jeff Bezos, business magnate Larry Ellison, and PayPal co-founder Peter Thiel.
The U.S. government, however, is lagging: The National Institutes of Health spent less than one percent of its $43 billion budget for the fiscal year of 2021 on the National Institute on Aging’s Division of Aging Biology. When you visit the division’s webpage you find that their mission statement carefully omits any mention of the possibility of slowing down the aging process.
There is a lack of political will and leadership on the issue, and the idea that we should seek to do something about aging is generally met with a great deal of suspicion and trepidation. In a large representative study conducted by the Pew Research Center in 2013, only 38% of the respondents said that they would want a treatment that could slow the aging process and allow them to live at least 120 years. Apparently, most people prefer, or at least do not mind, to age and die within a natural lifespan. This result has been confirmed by smaller studies and it is, I think, surprising. Are we not supposed to live in a youth-culture? Are people not supposed to want to stay young and alive forever? Is self-preservation not the strong drive we have always assumed it to be?
We are inundated and saturated with an ideology of death-acceptance.
In my book, The Case against Death, I suggest that we have been culturally conditioned to think that it is virtuous to accept aging and death. We are taught to believe that although aging and death seem gruesome, they are what is best for us, all things considered. This is what we are supposed to think, and the majority accept it. I call this the Wise View because death acceptance has been the dominant view of philosophers since the beginning. Socrates compared our earthly life to an illness and a prison and described death as a healer and a liberator. The Buddha taught that life is suffering and that the way to escape suffering is to end the cycle of birth, death and rebirth. Stoic philosophers from Zeno to Marcus Aurelius believed that everything that happens in accordance with nature is good, and that therefore we should not only accept death but welcome it as an aspect of a perfect totality.
Epicureans agreed with these rival schools and famously argued that death cannot harm us because where we are, death is not, and where death is we are not. We cannot be harmed if we are not, so death is harmless. The simple view that death actually can harm us greatly is one of the least philosophical views one can hold.
In The Case Against Death, philosopher Ingemar Patrick Linden argues that we frown on using science to prolong healthy life only because we're culturally conditioned to think that way.
Many of the stories we tell promote the Wise View. One of the earliest known pieces of literature, the Epic of Gilgamesh, follows Gilgamesh on a quest for eternal life ending with the wisdom that death is the destiny of man. Today we learn about the tedium of immortality from the children’s book Tuck Everlasting by Natalie Babbitt, and we are warned about the vice of wanting to resist death in other books and films such as J.K Rowling’s Harry Potter, where Voldemort must kill Harry as a step towards his own immortality; C.S. Lewis’ The Chronicles of Narnia where the White Witch has gained immortal youth and madness in equal measures; J.R.R. Tolkien’s Lord of the Rings trilogy where the ring extends the wearer’s life but can also destroy them, as exemplified by the creep Gollum; and Doctor Strange where life extension is the one magical power that is taboo. In Star Wars, Yoda, a stereotype of the sage, teaches us the wisdom handed down by philosophers and prophets: “Death is a natural part of life. Rejoice for those around you who transform into the Force. Mourn them do not. Miss them do not.”
We are inundated and saturated with an ideology of death-acceptance. Can the dear reader name one single story where the hero is pursuing anti-aging, longevity or immortality and the villain tries to stop her?
The Wise View resonates with us partly because we think that there is nothing we can do about aging and death, so we do not want to wish for what we cannot have. Youth and immortality are sour grapes to us. Believing that death is, all things considered, not such a bad thing, protects us from experiencing our aging and approaching death as a gruesome tragedy. This need to escape the thought that we are heading towards a personal catastrophe explains why many are so quick to accept arguments against radical life extension, despite their often glaring weaknesses.
One of the most common objections to radical life extension is that aging and death are natural. The problem with this argument is that many things that are natural are very bad, such as cancer, and other things that are not natural are very good, such as a cure for cancer. Why are we so sure that cancer is bad? Because we assume that it is bad to die. Indeed, nothing is more natural than wanting to live. We seem to need philosophers and story tellers to talk us out of it and, in the words of a distinguished bioethicist, “instruct and somewhat moderate our lust for life.”
Another standard objection is that we need a deadline, and that without death we could postpone every action forever. “Death brings urgency and seriousness to life,” say proponents of this view, but there are several problems with this argument. Even if our lives were endless, there would still be many things we would have to do at a certain time, and that could not be redone, for example, saving our planet from being destroyed, or becoming the first person on Venus. And if we prefer pleasant endless lives over unpleasant endless ones, we will have to exercise, eat right, keep our word, develop our talents, show up for time at work, pay our taxes by the due date, remember birthdays, and so on.
The Wise View provides us with a feel-good bromide for the anxiety created by the foreknowledge of our decay and death by telling us that these are not evils, but blessings in disguise. Once perhaps an innocuous delusion, today the view stands in the way of a necessary societal commitment to research that can prolong our healthy life.
Besides, even if we succeeded in ending aging, we would still die from other causes. Given the rate of accidental deaths we would be fortunate to live to age 2000 all things equal. So even if, contrary to what I have argued, we do need a deadline, we can still argue that the natural lifespan that we now labor under is inhuman and that it forces each human to limit her ambitions and to become only a fragment of all that she that could have been. Our tight time constraint imposes tragic choices and inflated opportunity costs. Death does not make life matter; it makes time matter.
The perhaps most awful argument against radical life extension is grounded in a pessimism that holds life in such little regard that it says that best of all is never to have born. This view was expressed by Ecclesiastes in the Hebrew Bible, by Sophocles and several other ancient Greeks, by the German philosopher Arthur Schopenhauer, and recently by, among others, the South African philosopher David Benatar who argues that it is wrong to bring children into the world and that we should euthanize all sentient life. Pessimism, one suspects, largely appeals to some for reasons having to do with personal temperament, but insofar as it is built on factual beliefs, they can be addressed by providing a less negatively biased understanding of the world, by pointing out that curing aging would decrease the badness that they are so hypersensitive to, and by reminding them that if life really becomes unbearable, they are free to quit at any time. Other means of persuasion could include recommending sleep, exercise and taking long brisk walks in nature.
The Wise View provides us with a feel-good bromide for the anxiety created by the foreknowledge of our decay and death by telling us that these are not evils, but blessings in disguise. Once perhaps an innocuous delusion, today the view stands in the way of a necessary societal commitment to research that can prolong our healthy life. We need abandon it and openly admit that aging is a scourge that deserves to be fought with the combined energies equaling those expended on fighting COVID-19, Alzheimer’s disease, cancer, stroke and all the other illnesses for which aging is the greatest risk factor. The fight to end aging transcends ordinary political boundaries and is therefore the kind of grand unifying enterprise that could re-energize a society suffering from divisiveness and the sense of a lack of a common purpose. It is hard to imagine a more worthwhile cause.
Researchers are looking to engineer chocolate with less oil, which could reduce some of its detriments to health.
Building a 3D tongue
The team began by building a 3D tongue to analyze the physical process by which chocolate breaks down inside the mouth.
As part of the effort, reported earlier this year in the scientific journal ACS Applied Materials and Interfaces, the team studied a large variety of human tongues with the intention to build an “average” 3D model, says Soltanahmadi, a lubrication scientist. When it comes to edible substances, lubrication science looks at how food feels in the mouth and can help design foods that taste better and have more satisfying texture or health benefits.
There are variations in how people enjoy chocolate; some chew it while others “lick it” inside their mouths.
Tongue impressions from human participants studied using optical imaging helped the team build a tongue with key characteristics. “Our tongue is not a smooth muscle, it’s got some texture, it has got some roughness,” Soltanahmadi says. From those images, the team came up with a digital design of an average tongue and, using 3D printed molds, built a “mimic tongue.” They also added elastomers—such as silicone or polyurethane—to mimic the roughness, the texture and the mechanical properties of a real tongue. “Wettability" was another key component of the 3D tongue, Soltanahmadi says, referring to whether a surface mixes with water (hydrophilic) or, in the case of oil, resists it (hydrophobic).
Notably, the resulting artificial 3D-tongues looked nothing like the human version, but they were good mimics. The scientists also created “testing kits” that produced data on various physical parameters. One such parameter was viscosity, the measure of how gooey a food or liquid is — honey is more viscous compared to water, for example. Another was tribology, which defines how slippery something is — high fat yogurt is more slippery than low fat yogurt; milk can be more slippery than water. The researchers then mixed chocolate with artificial saliva and spread it on the 3D tongue to measure the tribology and the viscosity. From there they were able to study what happens inside the mouth when we eat chocolate.
The team focused on the stages of lubrication and the location of the fat in the chocolate, a process that has rarely been researched.
The artificial 3D-tongues look nothing like human tongues, but they function well enough to do the job.
Courtesy Anwesha Sarkar and University of Leeds
The oral processing of chocolate
We process food in our mouths in several stages, Soltanahmadi says. And there is variation in these stages depending on the type of food. So, the oral processing of a piece of meat would be different from, say, the processing of jelly or popcorn.
There are variations with chocolate, in particular; some people chew it while others use their tongues to explore it (within their mouths), Soltanahmadi explains. “Usually, from a consumer perspective, what we find is that if you have a luxury kind of a chocolate, then people tend to start with licking the chocolate rather than chewing it.” The researchers used a luxury brand of dark chocolate and focused on the process of licking rather than chewing.
As solid cocoa particles and fat are released, the emulsion envelops the tongue and coats the palette creating a smooth feeling of chocolate all over the mouth. That tactile sensation is part of the chocolate’s hedonistic appeal we crave.
Understanding the make-up of the chocolate was also an important step in the study. “Chocolate is a composite material. So, it has cocoa butter, which is oil, it has some particles in it, which is cocoa solid, and it has sugars," Soltanahmadi says. "Dark chocolate has less oil, for example, and less sugar in it, most of the time."
The researchers determined that the oral processing of chocolate begins as soon as it enters a person’s mouth; it starts melting upon exposure to one’s body temperature, even before the tongue starts moving, Soltanahmadi says. Then, lubrication begins. “[Saliva] mixes with the oily chocolate and it makes an emulsion." An emulsion is a fluid with a watery (or aqueous) phase and an oily phase. As chocolate breaks down in the mouth, that solid piece turns into a smooth emulsion with a fatty film. “The oil from the chocolate becomes droplets in a continuous aqueous phase,” says Soltanahmadi. In other words, as solid cocoa particles and fat are released, the emulsion envelops the tongue and coats the palette, creating a smooth feeling of chocolate all over the mouth. That tactile sensation is part of the chocolate’s hedonistic appeal we crave, says Soltanahmadi.
Finding the sweet spot
After determining how chocolate is orally processed, the research team wanted to find the exact sweet spot of the breakdown of solid cocoa particles and fat as they are released into the mouth. They determined that the epicurean pleasure comes only from the chocolate's outer layer of fat; the secondary fatty layers inside the chocolate don’t add to the sensation. It was this final discovery that helped the team determine that it might be possible to produce healthier chocolate that would contain less oil, says Soltanahmadi. And therefore, less fat.
Rongjia Tao, a physicist at Temple University in Philadelphia, thinks the Leeds study and the concept behind it is “very interesting.” Tao, himself, did a study in 2016 and found he could reduce fat in milk chocolate by 20 percent. He believes that the Leeds researchers’ discovery about the first layer of fat being more important for taste than the other layer can inform future chocolate manufacturing. “As a scientist I consider this significant and an important starting point,” he says.
Chocolate is rich in polyphenols, naturally occurring compounds also found in fruits and vegetables, such as grapes, apples and berries. Research found that plant polyphenols can protect against cancer, diabetes and osteoporosis as well as cardiovascular ad neurodegenerative diseases.
Not everyone thinks it’s a good idea, such as chef Michael Antonorsi, founder and owner of Chuao Chocolatier, one of the leading chocolate makers in the U.S. First, he says, “cacao fat is definitely a good fat.” Second, he’s not thrilled that science is trying to interfere with nature. “Every time we've tried to intervene and change nature, we get things out of balance,” says Antonorsi. “There’s a reason cacao is botanically known as food of the gods. The botanical name is the Theobroma cacao: Theobroma in ancient Greek, Theo is God and Brahma is food. So it's a food of the gods,” Antonorsi explains. He’s doubtful that a chocolate made only with a top layer of fat will produce the same epicurean satisfaction. “You're not going to achieve the same sensation because that surface fat is going to dissipate and there is no fat from behind coming to take over,” he says.
Without layers of fat, Antonorsi fears the deeply satisfying experiential part of savoring chocolate will be lost. The University of Leeds team, however, thinks that it may be possible to make chocolate healthier - when consumed in limited amounts - without sacrificing its taste. They believe the concept of less fatty but no less slick chocolate will resonate with at least some chocolate-makers and consumers, too.
Chocolate already contains some healthful compounds. Its cocoa particles have “loads of health benefits,” says Soltanahmadi. Dark chocolate usually has more cocoa than milk chocolate. Some experts recommend that dark chocolate should contain at least 70 percent cocoa in order for it to offer some health benefit. Research has shown that the cocoa in chocolate is rich in polyphenols, naturally occurring compounds also found in fruits and vegetables, such as grapes, apples and berries. Research has shown that consuming plant polyphenols can be protective against cancer, diabetes and osteoporosis as well as cardiovascular and neurodegenerative diseases.
“So keeping the healthy part of it and reducing the oily part of it, which is not healthy, but is giving you that indulgence of it … that was the final aim,” Soltanahmadi says. He adds that the team has been approached by individuals in the chocolate industry about their research. “Everyone wants to have a healthy chocolate, which at the same time tastes brilliant and gives you that self-indulging experience.”
Probiotic bacteria can be engineered to fight antibiotic-resistant superbugs by releasing chemicals that kill them.
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 Lancet study 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
Adobe Stock
Seek and destroy
As the field of synthetic biology developed, scientists began using engineered bacteria to tackle superbugs. They first focused on Vibrio cholerae, which in 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. cholerae strains 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 by John March, professor of biological and environmental engineering, developed a novel strategy to combat V. cholerae. They genetically engineered E.coli to eavesdrop 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 often drug-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. obeum in 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 bacteria commonly found in yogurt called Lactococcus lactis to treat cholera.
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.”