Wander down a supplement aisle at your local pharmacy or hop on the internet, and it’s not hard to find products that promise to “slow the normal signs of aging” or that offer “long-term well-being at the cellular level.” Humans have been trying to outsmart the inevitable for centuries.

The alchemists began their search for an elixir for eternal youth some 800 years ago, when they tried to make the philosophers’ stone by converting base metals into gold.Most modern-day antiaging remedies have remarkable parallels to their alchemical predecessors: Both can yield a fast buck, but neither is based on science proven to work in humans.

After hundreds of years of effort, there is still no miracle pill that can turn back time, despite the claims of zealous entrepreneurs. Some pseudoaging treatments over the years have been risky, capable of doing more harm than good—for example, injections of human growth factor or grafts of chimpanzee testicular tissue to rejuvenate aging bodies. Others, such as red wine’s resveratrol—which spawned an industry that peaked at $50 million in 2012—have just yielded “disappointing scientific results,” says Joao Pedro De Magalhaes, who studies aging at the University of Liverpool. But there’s a silver lining to the snake oil, he adds. “If there’s such a big market for stuff that doesn’t work, imagine how much money there would be for something that does.”

Given the financial incentive and the enormous demand, one might ponder why aging science still has not yielded clinically proven therapies to combat our decline. The short answer is that aging is mind-bogglingly complicated. Thousands of genes are involved in human deterioration. And whether we fast, exercise, experience chronic stress, or smoke, our lifestyle choices can sway our DNA’s late-life forecast for good and bad. Then there’s the fact that every time scientists uncover new layers to our biology, such as epigenetics, micro-RNA, and the microbiome, they realize that these influence human aging too. Add to this the challenge of logistics (aging experiments take decades in humans) and financial pressures (any clinical trial for an aging drug would cost trillions of dollars because of this time span), and you wonder why scientists haven’t just collectively crawled under their lab benches in the fetal position.

Despite the challenges, there’s hope for those who want to live healthier for longer. Researchers are uncovering ways to turn back time on aging cells, and several existing drugs are being reborn as antiaging candidates. And big players with deep pockets, including Google and the biotech guru Craig Venter, have jumped into the aging game, eager to wield genomics, big data tools, and machine-learning techniques as weapons against humanity’s oldest rival.

“Age is the greatest risk factor for nearly every major cause of mortality in developed nations,” argues Matt Kaeberlein, who studies aging at the University of Washington, in a 2014 commentary in Science (DOI: 10.1126/science.aad3267).

Over the past few centuries, modern medicine and other innovations have doubled our life span, but these treatments have focused on curing diseases that spring up during old age, such as cancer and heart disease, rather than decoding the underlying cellular and molecular processes that make the elderly vulnerable to these afflictions in the first place.

Humans are living longer, but we’re not always healthy enough to enjoy the extra years.“Many families struggle to care for elderly relatives who survive for years or decades with reduced quality of life, while nations devote an increased proportion of finite resources toward medical care for aging populations,” Kaeberlein says. According to the World Health Organization, in most countries the proportion of people over 60 is rising faster than any other age group: Seniors are expected to be one-fifth of the global population by 2050, double the proportion now. Clearly, there’s a pressing need to find scientifically sound ways to help our aging population live healthier for longer, as well as to answer fundamental questions such as why we age in the first place.

The inside view on aging Researchers have peered into the human body in search of ways to thwart our inevitable decline. Here are some of the most promising discoveries. Caloric restriction

In every organism studied by aging researchers—including mice, flies, worms, and even yeast—regular episodes of prolonged fasting have extended life span and activated cellu- lar protection pathways. But there’s always a catch: Lab organisms are often clones. When researchers tried caloric restriction in genetically diverse mice, the effects were mixed. In humans, caloric restriction can protect against diabetes, hypertension, and cardiovascular diseases, but our immune system becomes less adept at fighting infections. Young blood

When researchers conjoined two mice so that they shared the same circulatory system—a medieval-sounding process called parabiosis—the results were bloody promising. The old mouse showed signs of rejuvenation while the young mouse showed signs of aging. Since then, researchers have been searching through young and old blood for molecules that might be responsible for these effects. Gut microbiome

When researchers compared the poop of frail elderly people with that of a similar but more robust control group, the frail folks had lower levels of short-chain fatty acids, which the microbes in our guts normally make from dietary fiber. These short-chain fatty acids, including acetate, butyrate, and propionate, are an important energy source for the colon. The frail subjects also had gut microbiomes depleted in species of bacteria that could do this chemical conversion. It raises the question: Could poop transplants alleviate some of the problems of old age? Some researchers think so. Senescent cells

When a cell begins to turn cancerous, the body sometimes makes it senescent: It’s allowed to live and secrete chemical messages to nearby cells, but it’s no longer allowed to divide. When enough senescent cells accumulate, their combined chemical cocktail can cause a variety of age-related problems, including heart disease. So researchers are looking to kill and clear these cells or to reprogram them. Mitochondria

This energy-producing organelle has been associated with aging for decades: Some of the first genes found to extend worm lifetimes coded for dysfunctional proteins in mitochondria. Researchers initially thought that dysfunctional mitochondria might help extend lives because they produce fewer harmful reactive oxygen species. As it turns out, it’s not that simple. Reactive oxygen species can also activate beneficial, life-extending protective stress responses. Telomeres

Like the plastic caps at the end of your shoelac- es, telomeres provide a protective cap to the ends of chromosomes. The trouble is, every time a cell divides, those caps shorten. The older you get, the shorter telomeres get, acting as a marker for the aging process. A variety of proteins are involved in telomere up-keep, including telomerase, which can help rebuild these shortened ends. Unfortunately, therapeutically prodding telomerase to do a better job often turns cells cancerous. The inside view on aging Researchers have peered into the human body in search of ways to thwart our inevitable decline. Here are some of the most promising discoveries. Caloric restriction

In every organism studied by aging researchers—including mice, flies, worms, and even yeast—regular episodes of prolonged fasting have extended life span and activated cellu- lar protection pathways. But there’s always a catch: Lab organisms are often clones. When researchers tried caloric restriction in genetically diverse mice, the effects were mixed. In humans, caloric restriction can protect against diabetes, hypertension, and cardiovascular diseases, but our immune system becomes less adept at fighting infections. Young blood

When researchers conjoined two mice so that they shared the same circulatory system—a medieval-sounding process called parabiosis—the results were bloody promising. The old mouse showed signs of rejuvenation while the young mouse showed signs of aging. Since then, researchers have been searching through young and old blood for molecules that might be responsible for these effects. Gut microbiome

When researchers compared the poop of frail elderly people with that of a similar but more robust control group, the frail folks had lower levels of short-chain fatty acids, which the microbes in our guts normally make from dietary fiber. These short-chain fatty acids, including acetate, butyrate, and propionate, are an important energy source for the colon. The frail subjects also had gut microbiomes depleted in species of bacteria that could do this chemical conversion. It raises the question: Could poop transplants alleviate some of the problems of old age? Some researchers think so. Senescent cells

When a cell begins to turn cancerous, the body sometimes makes it senescent: It’s allowed to live and secrete chemical messages to nearby cells, but it’s no longer allowed to divide. When enough senescent cells accumulate, their combined chemical cocktail can cause a variety of age-related problems, including heart disease. So researchers are looking to kill and clear these cells or to reprogram them. Mitochondria

This energy-producing organelle has been associated with aging for decades: Some of the first genes found to extend worm lifetimes coded for dysfunctional proteins in mitochondria. Researchers initially thought that dysfunctional mitochondria might help extend lives because they produce fewer harmful reactive oxygen species. As it turns out, it’s not that simple. Reactive oxygen species can also activate beneficial, life-extending protective stress responses. Telomeres

Like the plastic caps at the end of your shoelac- es, telomeres provide a protective cap to the ends of chromosomes. The trouble is, every time a cell divides, those caps shorten. The older you get, the shorter telomeres get, acting as a marker for the aging process. A variety of proteins are involved in telomere up-keep, including telomerase, which can help rebuild these shortened ends. Unfortunately, therapeutically prodding telomerase to do a better job often turns cells cancerous. Credit: Will Ludwig/C&EN/Shutterstock

Why do we age, anyway?

“Aging is weird,” says Linda Partridge, director of the Institute of Healthy Ageing at University College London. “If nature can develop a healthy, perfectly useful body in the first place, you’d think it would be a lot simpler to maintain. So why on earth do bodies run down and die?” Throughout most of the 20th century, Partridge says, researchers tried to understand why evolution let us age at all.

Most in the field now agree with a theory on aging initially proposed in the 1950s whose arduous name, antagonistic pleiotropy, belies its simplicity. The theory is based on the idea that “for 99.999% of human evolutionary history, our life span was extremely short,” explains Judy Campisi of the Buck Institute for Research on Aging.

“Our predecessors never died of cancer or heart disease,” Campisi says. “They died of violence, starvation, exposure, and infectious disease.” Antagonistic pleiotropy argues that evolution optimized most of our traits so we could survive long enough to produce offspring. “These same traits, however, could be deleterious in old age,” Campisi adds. “For example, calcium in blood helps the bones of young hunter-gatherers heal easily so they can get back to hunting. But if you happen to live to your 60s, that calcium is deposited in your arteries, leading to blockages and stiffness. The very same trait that served you well in your 30s doesn’t in your 60s.”

As it became clear that aging was a long-term side effect of the more pressing goal of ensuring reproduction, researchers had the sense that aging was too complex to interfere with. But by the late 1990s, researchers had discovered that simple mutations in single genes could double, triple, and even more radically increase the life span of worms, explains Siegfried Hekimi, a researcher on aging at McGill University. Soon thereafter, Partridge found single gene mutations that could extend life span in fruit flies; others found them in mice and other organisms.

The discovery that you could get a huge effect by mutating single genes galvanized the field, Partridge says. If simple genetic interventions could extend animals’ lifetimes and keep them healthier for longer, certainly drugs could also be targeted to the proteins produced from these genes. “What seemed like an intractable process turned out to be very malleable,” Partridge adds. “People were surprised and very excited.”

Researchers began digging into the role these genes play in our bodies, discovering that they are enmeshed in a variety of biochemical pathways, from those that run processes deep in a cell’s nucleus or mitochondria to those that manage our overall physiology and metabolism. Others took it as a sign that human life span extension was also possible. For example, in a 2005 TED Talk and elsewhere, Aubrey de Grey, who now runs the California-based SENS Research Foundation, claimed that humans could live 1,000 years if only there were enough funding to develop life-extension strategies. Some found these assertions inspiring; others reeled.

Extending life span is out; improving ‘health span’ is in

“If you talk about increasing life span, some people say, ‘Whoa, what about overpopulation? I don’t want to be old for 100 years,’ ” Liverpool’s De Magalhaes says. “Life span extension raises natural concerns.”

“On the other hand, if you say, ‘I don’t want you to develop Alzheimer’s, ever,’ nobody is going to argue against that,” he says. As a result, many in the field of aging have stopped talking about extending life span, preferring to describe their goal as extending “health span,” especially because age is the number one risk factor for many diseases.

The semantics of emphasizing health span over life span is also about sticking to the facts, Campisi says. “At this stage we simply have no idea whether it will be possible to extend human life span. But there is very promising evidence that we can extend health span,” she adds. “Increasing health span is an easier goal with a decent track record; that’s pretty much the basis of all biomedical science.”

As some scientists cataloged age-related genes in a range of organisms over the past two decades—a database called GenAge now has more than 1,000 entries—others began delving into the multifaceted roles these genes play in our bodies.

For example, genes related to aging are involved in our overall metabolism. Multiple studies in humans and lab animals show that if we exercise and restrict our calories, we can extend life span and help reduce the risk of age-related disease. Genes affecting age also sway our body’s hormone signaling, the ability of our stem cells to regenerate new tissue and blood, and the functioning of our cells’ energy-producing mitochondria. Perhaps most famously, some age-related genes interfere with the length of our telomeres, the DNA sequences that cap our chromosomes and whose shrinking is a gauge for the human aging process.

Knowing about these connections and knowing that humans often have a hard time sticking with diets and exercise, researchers are now mapping these many biological pathways to strategically target them with drugs.

To date, scientists have found hundreds of compounds that seem to tweak pathways involved in aging, which De Magalhaes and his collaborators have recently assembled into a database called DrugAge. “You go to conferences, and it seems like everyone has a compound they’re focusing on that’s increased life span in their model system,” whether that’s a cell or an animal, he says. “Of course there’s a very big gap between increasing life span in model systems and actually developing clinical applications for humans,” he adds.

One problem is what many in the aging field call “the Goldilocks problem.” Like the little protagonist in the fairy tale who was very particular about her porridge being not too hot and not too cold, biological cells also need things to be just right to stay healthy. Case in point: those telomeres.

Researchers have been intrigued by the fact that as human telomeres get shorter, people’s risk of death and of many common age-related diseases rises. So one would think that any drug that activates the enzymes involved in rebuilding telomeres would be an instant blockbuster.

Yet scientists have observed that chemically pushing telomerase enzymes to lengthen telomeres has a tendency to make cells cancerous. And many of the biological processes that impact aging have the same Achilles’ heel: Tweak them a little and the cost of attempted immortality is cancer.

The more we peer closely at the biological mechanisms that influence aging, the more complicated they appear.

Decoding the complexity

“We don’t fundamentally know the molecular basis of aging. We just tweak with the consequences,” McGill University’s Hekimi says. “We don’t really know exactly what kicks it all off.” But he and many in the field suspect that the onset of aging is tied to genome damage. Over time, our telomeres erode, our DNA is exposed to mutagenic chemicals that genome-repair machinery can’t fix, and viral DNA integrated into the genome starts jumping around, causing further damage, University College London’s Partridge explains. “Even the way DNA is packed into chromosomes starts to break down.”

“Generally, things go to hell in a bucket in the genome,” which in turn affects cellular processes, Partridge says. “Cells talk to other cells,” she adds. For example, aging cells that are “senescent”—meaning they stop dividing but don’t die—send out cell-signaling molecules to alert their next-door neighbors about their current status. “It’s a very complicated process, with other parallel, interacting processes,” Partridge says.

One of the most promising avenues of aging research is the inroads researchers have made in understanding senescent cells, Partridge says. Like aging in general, senescent cells evolved to benefit young, reproductive members of the species, but they become increasingly problematic for the elderly.

“When you’re young, senescent cells are programmed to stop dividing if they are in danger of becoming cancerous,” says the Buck Institute’s Campisi, who discovered the first biomarker of senescent cells, a β-galactosidase protein that these cells contain at high levels. Not only that, but senescent cells also secrete a host of molecules that, in young people, stimulate regeneration and repair, Campisi says.


But over time, as more and more cells turn senescent, levels of these secreted molecules stop positively influencing their neighbors and begin causing inflammation. Groups of senescent cells produce such high levels of these chemicals that other, normal cells are persuaded to turn senescent. The secreted cocktail can even activate a variety of age-related pathologies, including heart disease and certain types of cancer—a disease that senescent cells evolved to thwart in the first place.

“The question is, is there anything we can do about senescent cells?” Campisi asks. Because they help protect us from cancer, “we certainly don’t want to obliterate them entirely,” she contends. But we don’t want to let them accumulate in old age either.

There’s been a recent “gold rush” of researchers identifying therapeutic compounds that target senescent cells and can periodically deactivate them in older people, says Peter L. J. de Keizer, who studies aging at Rotterdam’s Erasmus University Medical Center. Keizer has pursued cell-penetrating peptides as a tool for destroying senescent cells. Others have investigated dietary flavonols, small interfering RNA, and the cancer drug dasatinib, to name a few of the many research routes being taken.

Start-up companies have also gotten in on the act. For example, Campisi and her collaborators launched a firm, Unity Biotechnology, which aims to clear senescent cells from the kidney, eyes, arteries, and joints using a compound called ABT-263 that had previously been investigated for cancer. Researchers at the Weizmann Institute for Science are on a similar track, using a sister compound called ABT-737. In 2016, they reported that ABT-737 could kill and clear senescent skin cells in mice, “leading to an increase in hair-follicle stem cell proliferation” (Nat. Commun. 2016, DOI: 10.1038/ncomms11190). The potential for hair regrowth would certainly be lucrative if it passes muster in humans.

“If chemists can come up with drugs that can kill senescent cells in humans, we think this is going to revolutionize modern medicine,” Campisi says. “No longer would you have a pill for your blood pressure and a pill for your glaucoma and a pill to stabilize your heart and a pill to improve your kidney function. You’d have a pill that would hit multiple problems that affect the elderly,” she says. “It is very unlikely that these are drugs that you would have to take every day. Just when enough senescent cells had accumulated again,” she adds.

Others are considering a different strategy for striking down senescent cells. Instead of trying to kill and clear senescent cells, some researchers want to reprogram them to a more youthful state. The idea is to erase cellular markers of senescence and aging in these cells. The approach, led by Juan Carlos Izpisua Belmonte at the Salk Institute for Biological Studies, is to borrow from strategies used by researchers who are reprogramming mature cells such as skin cells to become so-called pluripotent stem cells—ones with the potential to become any cell type in the body.

In a recent paper in Cell, Belmonte and colleagues announced that they had managed to reprogram senescent cells in mice by temporarily activating four genes known to make stem cells pluripotent (2016, DOI: 10.1016/j.cell.2016.11.052). The four genes remodel a cell’s epigenetic markings, removing signs of aging at a cellular level. The treated mice had rejuvenated muscle, pancreas, and spleen tissue, as well as more youthful skin—and they lived longer too. “We are now trying to develop novel ways to achieve cellular rejuvenation using combinations of chemicals” rather than by invasively altering genes, Belmonte tells C&EN. “We think these chemical approaches might be in human clinical trials in the next 10 years.”

Clinical horizons

Although it’s obvious that any antiaging treatment will need to successfully pass human clinical trials to be considered viable by the U.S. Food & Drug Administration and other regulatory agencies, the path forward is unclear.

“Among the foremost challenges, aging is not formally considered a disease by the FDA and the prospects of testing whether drugs extend human lifespan directly promises to be a long and exorbitantly expensive process,” write Brian K. Kennedy and Juniper K. Pennypacker from the Buck Institute in a 2015 commentary (Oncotarget, DOI: 10.18632/oncotarget.3173).

A clinical trial for an antiaging therapy could cost trillions of dollars, the sort of money precious few investors—if any—would be willing to risk on a single, putative drug candidate. Yet, Kennedy argues, “it is critical for aging research to enter the clinic.”

He and others in the field of aging suspect that potential antiaging drugs whose long-term safety has been established are already on the shelves of pharmacies. In fact, one highly publicized project, led by Nir Barzilai of the Albert Einstein College of Medicine and others, aims to kick-start the first antiaging clinical trial focused on a longtime diabetes drug.

Since the 1950s, metformin has been given preventively to people at risk for type 2 diabetes because it decreases liver glucose production and boosts insulin sensitivity.

Two of aging science’s newest animal models: The naked mole rat, which has an impressive life span and cancer resistance, and the African killifish, the shortest-lived vertebrate in captivity.

Studying the long-term effects of the drug, Craig Currie of Cardiff University and coworkers in 2014 reported that people with type 2 diabetes taking metformin lived longer than did a control group of similar people without diabetes, who therefore didn’t take the drug (Diabetes Obes. Metab., DOI: 10.1111/dom.12354).

In other words, people lived longer with diabetes than without it, as long as they were taking metformin. Currie’s study and many others have provided enticing evidence that metformin might protect against basic aging processes, not just type 2 diabetes.

“One wonders whether many of the drugs used to treat early-stage chronic disease may be effective at least in part because they target the biggest risk factor for these diseases: aging itself,” Kennedy writes about the study.

Kennedy and others in academia and industry also have their eye on another existing drug, rapamycin, as a possible antiaging contender. Rapamycin was first discovered in Easter Island soil bacteria in the 1980s, and its analogs are used as an immune system suppresant during organ transplant and as a cancer drug. For years, researchers have also known that rapamycin extends the life span of mice.

A few years ago, researchers at Novartis took things to a new level when they evaluated whether taking a rapamycin analog called RAD001 could affect aging in humans. In a 2014 study—which is widely touted by scientists who research aging, whether they focus on rapamycin or not—Joan Mannick and her Novartis colleagues reported that taking the rapamycin analog rejuvenated the immune systems of elderly people (Sci. Trans. Med. 2014, DOI: 10.1126/scitranslmed.3009892).

The work was based on a common problem faced by seniors: They don’t respond particularly well to influenza vaccination. As we age, our immune system isn’t as adept at being trained to identify new pathogens. On the basis of experiments in mice, the Novartis team gave elderly clinical trial subjects the company’s rapamycin analog for six weeks. Then they waited two weeks for the patients to clear the drug before administering the flu vaccine. What they saw was a significantly improved response to the vaccine—the patients’ bodies produced higher levels of antibodies to the flu strains in the vaccine than usual.

The work has further galvanized research on the protein that rapamycin targets, a kinase called mTOR. This kinase plays a role in a variety of pathways, which is why medicinal chemists are trying to design rapamycin analogs—rapalogs—that are more specific to certain cellular situations. Not only does mTOR tweak immune systems, but it also suppresses some senescent cells from secreting their cocktail of problematic molecules. Researchers have also discovered that the enzyme plays a role in the positive effects of caloric restriction.

Toward personalized treatment

Could targeting mTOR be the path toward an antiaging blockbuster? Could rapamycin and its rapalogs help us all live healthier for longer? Campisi cautions that “there’s not going to be a treatment that works on everyone. There will be no vaccine to eradicate aging like you can eradicate small pox.” The reason: We’re all different. You don’t have to bring a cohort of 70-year-old humans into a room to know that one might be marathon-ready while another might be on dialysis.

Aging will probably be treatable only in a personalized way, De Magalhaes says. “Say I have a susceptibility to Alzheimer’s disease, but I am less susceptible to cancer. Maybe there’s a drug that protects me from Alzheimer’s disease even though it slightly increases my risk for cancer.”

That’s where big data can come in, De Magalhaes adds: “to help establish personalized medicine so we can tailor preventive measures and treatments to different individuals.”


Big data are behind the start-up Human Longevity, Craig Venter’s newest venture. The firm plans to sequence the genomes of 40,000 people per year and use the data to find keys for human health, which inevitably includes aging.

Last year, the company published the results of its first deep sequencing of 10,000 human genomes. In that report, the firm stated that it had identified “over 150 million human variants, a majority of them rare and unknown. These data identify sites in the genome that are highly intolerant to variation—possibly essential for life or health” (Proc. Nat. Acad. Sci. USA 2016, DOI: 10.1073/pnas.1613365113).

These are the kind of data that might make those developing machine-learning tools and other computational methods salivate. As the amount of aging-related data increases, researchers using machine-learning tools have more to work with and a better chance of uncovering new truths in the biology of aging, explains De Magalhaes.

To date, machine-learning research on aging has led to a variety of predictions, for example, expanding lists of pro-longevity proteins. And machine-learning approaches to aging aren’t just academic. Google has also gotten into the game. Harnessing its enormous resources, Google started a company in 2013 called Calico, “whose mission is to harness advanced technologies to increase our understanding of the biology that controls lifespan,” according to its website.

The company has been inking deals around the country with academic institutions such as the Broad Institute of Harvard University and Massachusetts Institute of Technology, the Buck Institute, and the University of Texas Southwestern Medical Center. And it’s made deals with other companies, such as a partnership with University of California start-up QB3 and a much reported $1.5 billion coinvestment with AbbVie, a Chicago-based drug developer.

Only a few details of Calico’s specific research plans have trickled out: The company’s website mentions machine learning, and it has hired expertise in this area of artificial intelligence. The firm also plans to use less-conventional animal models in its laboratory research, such as the naked mole rat, whose ugliness is as impressive as its long life span and cancer resistance.

Although the company promises to devise interventions that enable people to lead longer and more healthful lives, many of the specifics of their research are “cards held very close to the chest,” Campisi says. Neither Calico nor Human Longevity responded to requests for interviews.

The entry of big players with big data and big money behind them makes it tempting to speculate that an integrated theory of aging may be possible. That would be nice, but don’t hold your breath, De Magalhaes says. “Twenty years ago I thought, yes, we’ll find a theory of everything for aging. Now I’ve changed my mind.” But that doesn’t make him or others in the field pessimistic about the field’s potential to deliver antiaging remedies.

“How much do we need to understand the process before we start to intervene in it?” Partridge asks. Many in the field point to the fact that no comprehensive theory of cancer exists, yet researchers have generated life-saving cancer treatments. “I would encourage the field to steer hard toward trying to find useful discoveries” that improve health span, Partridge says. “We need some big medical hits from the research being done. Because to date, there’s not yet been a breakthrough for treating humans.”

In the meantime, Partridge forces herself to exercise, as her “physician, heal thyself” antiaging treatment. “When people ask me how to stay young,” Campisi adds, “I say, ‘exercise, don’t smoke, eat your veggies, and choose your grandparents wisely.’ ”