COVID-19 poses the greatest threat to older people, but vaccines often don’t work well in this group. Scientists hope drugs that rejuvenate the immune system will help.

Unlike fine wine, the human body does not improve with age. Hearing fades, skin sags, joints give out. Even the body’s immune system loses some of its vigour.

This phenomenon, known as immunosenescence, might explain why older age groups are so hard-hit by COVID-19. And there is another troubling implication: vaccines, which incite the immune system to fight off invaders, often perform poorly in older people. The best strategy for quelling the pandemic might fail in exactly the group that needs it most.

Scientists have known for decades that ageing immune systems can leave the body prone to infection and weaken their response to vaccines. In June, the US Food and Drug Administration announced that a COVID-19 vaccine would have to protect at least half the vaccinated individuals to be considered effective, but protection in older adults might not even meet that bar. “No vaccine is going to be as effective in the elderly as it is in young people,” says Matt Kaeberlein, a gerontologist at the University of Washington in Seattle. “That’s an almost certainty.”

The human immune system is mind-bendingly complex, and ageing affects nearly every component. Some types of immune cell become depleted: for example, older adults have fewer naive T cells that respond to new invaders, and fewer B cells, which produce antibodies that latch on to invading pathogens and target them for destruction. Older people also tend to experience chronic, low-grade inflammation, a phenomenon known as inflammageing (see ‘Depleted defences’). Although some inflammation is a key part of a healthy immune response, this constant buzz of internal activation makes the immune system less responsive to external insults. “This overarching, chronic inflammatory state is what’s driving much of the immune dysfunction that we see,” says Kaeberlein. The upshot is a poorer reaction to infections and a dulled response to vaccines, which work by priming the immune system to fight off a pathogen without actually causing disease.

With about 50 COVID-19 vaccine candidates currently being tested in humans, researchers say it’s not yet clear how they will fare in older adults. In its phase I study of 40 people aged 56 and over, Moderna in Cambridge, Massachusetts, reported that its candidate mRNA-1273 elicited similar antibody levels as those elicited in a younger age group¹. The Chinese biotech Sinovac in Beijing, which trialled its CoronaVac candidate in a phase I/II study that included 421 adults between 60 and 89 years of age, announced in a press release on 9 September that it seems to work as well in older adults as it does in younger ones. However, a phase I study by international pharma company Pfizer and BioNTech in Mainz, Germany, showed that their vaccine BNT162b2 provokes an immune response that is about half as strong in older adults as it is in younger ones². The older adults still produced more antibodies in response to the vaccine than people of a similar age who had had COVID-19, but it’s not known how these levels translate into protection from the virus.

Most COVID-19 vaccine trials include at least some older adults. But a recent analysis of 18 such trials found that the risk of exclusion is high³. More than half had age cut-offs and many were at risk of excluding older participants for other reasons, including underlying conditions.

If COVID-19 vaccines perform less well in older adults, researchers might be able to find ways to tweak the shot itself to elicit a stronger response. Some influenza vaccines, for instance, include immune-boosting ingredients or higher doses of the viral antigen. But some scientists say there is a better option. They are developing and testing drugs that could improve how older adults respond to vaccines and might also help them fight viruses more effectively in the first place. Rather than working with the limitations of the ageing immune system, they are planning to rejuvenate it.

Forever young

Many researchers have grown old trying to pinpoint ways to reverse the ageing process. In the past decade, however, they have made serious progress in identifying particular molecular targets that might help in this quest.

One promising class of anti-ageing drug acts on pathways involved in cell growth. These drugs inhibit a protein known as mTOR. In the laboratory, inhibiting mTOR lengthens lifespan in animals from fruit flies to mice. “mTOR is one of probably multiple biologic mechanisms that contribute to why we age and why our organ systems start to decline,” says Joan Mannick, co-founder and chief medical officer of resTORbio, a biotech company based in Boston, Massachusetts, that aims to develop anti-ageing therapies.

In a study published in 2018 and carried out when Mannick was at the Novartis Research Institutes in Cambridge, Massachusetts, she and her colleagues tried damping down mTOR in elderly adults to see if this could improve immune function and lower infection rates⁴. The 264 participants received a low-dose mTOR inhibitor or a placebo for six weeks. Those who received the drug had fewer infections in the year after the study and an improved response to the flu vaccine. On the basis of her work on mTOR inhibition, Mannick, by then at resTORbio, launched a phase III trial in 2019 to see if a similar mTOR inhibitor called RTB101 could stave off respiratory illnesses in older adults.

That trial failed to show the desired effect, perhaps because infections were monitored by self-report of symptoms rather than requiring a lab test to confirm infection, as in the earlier trial. That created “a lot more noise”, says Ilaria Bellantuono, co-director of the Healthy Lifespan Institute at the University of Sheffield, UK, who was not involved in the trial. “A much bigger group would have been required to see a difference.”

Still, the data from this and an earlier trial suggested that participants who received the mTOR inhibitor had fewer severe infections from circulating coronaviruses and recovered faster from them than the placebo group. The trials pre-date the emergence of SARS-CoV-2, but they suggest that RTB101 could lessen the severity of infection. resTORbio is now testing that idea in 550 nursing-home residents aged 65 and over.

RTB101 is similar to an already approved mTOR inhibitor, the immune-suppressing drug rapamycin. At least four other groups are testing rapamycin in small numbers of infected individuals as a possible COVID-19 therapy; one group is trialling the drug exclusively in adults aged 60 or older.

The type 2 diabetes drug metformin also dampens down mTOR’s activity, albeit indirectly. Some studies suggest that people who take metformin are less likely to be hospitalized or die if they contract COVID-19. A small retrospective study in China found that the mortality among hospitalized individuals with COVID-19 taking metformin was 2.9% compared with 12.3% in people who didn’t take the drug⁵. Researchers at the University of Minnesota in Minneapolis analysed data on hospitalized individuals with COVID-19 who had an average age of 75, some of whom were already taking metformin for obesity or diabetes. They found a significant reduction in mortality among women taking metformin, but not among men⁶.

Carolyn Bramante, an obesity researcher who led the University of Minnesota study, points out that diseases such as diabetes and obesity lead to some of the same immune deficits as occur in older age. She and her colleagues plan to launch a trial of 1,500 people aged 30 and over to determine whether metformin could help stave off SARS-CoV-2 infection or prevent the worst outcomes in people already infected.

Meanwhile, Jenna Bartley, who studies ageing at the University of Connecticut in Storrs, is assessing whether metformin can boost responses to flu vaccine in a small trial of older adults. The idea, based on her work in mice, is that metformin can improve the energy metabolism of the T cells of the immune system, making them better at detecting new threats. Bartley has finished collecting data, but because her lab was shut down owing to COVID-19, she won’t have the results analysed for a few more weeks.

If metformin works against COVID-19, researchers will still have to tease out why. Kaeberlein points out that no one is quite sure how metformin works because it has so many targets. “It’s about the dirtiest of dirty drugs out there,” he says. It was originally used as an anti-influenza drug; Bramante says it helps tamp down inflammation. Aside from the mechanistic unknowns, the advantage is that metformin has been used for decades and is generally safe. Children can take it, as can pregnant women. “Metformin is a medication that you actually could give prophylactically for 12 months without having to do any follow-up,” Bramante says, “and it costs less than US$4 a month.”

Soothing balm

mTOR is a classic anti-ageing target, but it’s far from the only one. In fact, many anti-ageing pathways seem to be linked, says James Kirkland, who studies cellular ageing and disease at the Mayo Clinic in Rochester, Minnesota. “That is, if you target one, you tend to affect all the rest,” he says. Many of the immune changes that come with ageing lead to the same result: inflammation. So researchers are looking at drugs that will calm this symptom.

Arne Akbar, an immunologist at University College London, has shown that the anti-inflammatory drug losmapimod, which is being developed as a therapy for muscular dystrophy, might help boost immunity. In a 2018 study, the researchers injected chickenpox virus into the skin of elderly adults⁷. Although these people had already been exposed to chickenpox, their immune response was lacklustre, hampered by excess inflammation. When the team gave the study participants losmapimod, it ratcheted down inflammation by about 70% and improved their immune responses.

In June, the company currently developing losmapimod — Fulcrum Therapeutics in Cambridge, Massachusetts — launched a 400-person phase III study to investigate whether the drug could prevent death and respiratory failure in older people hospitalized with COVID-19.

“Senescence is really a key factor in ageing,” says Eric Verdin, president and chief executive of the Buck Institute for Research on Aging in Novato, California, who is not involved in the fisetin research. No senolytics have currently been approved for clinical treatment, however. “This is one area that has been much less studied,” he says.

Kaeberlein says it’s likely that most companies will pursue anti-ageing drugs as therapies before they test them as prophylactics. “It’s much easier to get a therapy approved in people who are already sick,” he says. He thinks that mTOR inhibitors hold the most promise. “If I had the power to go back to the beginning of this whole COVID pandemic and try one thing, I’d pick mTOR inhibitors — rapamycin specifically,” he says. According to his back-of-the-envelope calculations, if rapamycin works in the same way in people as it does in mice, it could reduce COVID-19 mortality by 90%.

Kirkland says he can envisage giving one of these anti-ageing drugs as a primer before vaccination. “We have to figure out ways to target fundamental ageing mechanisms at around the time that we’re vaccinating people,” he says, “but we have to find ways of doing this that are safe and effective.”

Added ingredients

If tweaking the immune system proves too challenging, there might be ways to juice up the vaccine itself. For flu, there are two vaccines aimed specifically at people over 65, which help worn immune systems to stage a response. One, Fluzone High-Dose, contains four times the standard amount of flu virus antigens, and the other, Fluad, relies on an immune-boosting molecule called an adjuvant.

A team led by vaccinologist Ofer Levy at Boston Children’s Hospital in Massachusetts is working on a COVID-19 vaccine specifically for older adults, using an in-vitro screening system to identify the best adjuvants. “Vaccines were typically developed as one-size-fits-all,” he says. But a lot of features — age, sex, and even the season — affect vaccine responses, Levy says. The best combinations of adjuvant and vaccine they find will be tested in mice and then in humans.

But, in general, developing medications to improve immune function seems like a much smarter strategy than creating vaccines specifically for elderly people, says Claire Chougnet, an immunologist at Cincinnati Children’s Hospital Medical Center in Ohio, who is studying inflammation in aged mice. Vaccine development is costly and time-intensive. “In the case of an emerging virus, when you want a quick response, that makes things even more complicated if you have to do two types of vaccine,” she says. Plus, individual vaccines target specific pathogens, but an immune-boosting medication could be used with any vaccine. “That could work for flu, that could work for COVID-19. That would work for COVID-25,” she says. The approach is “extremely versatile”.

Verdin agrees that supporting the older immune system should be a priority. “I think the net result of all this will be renewed interest in understanding the defect in the immune response in the elderly.” That has implications not only for the coronavirus, but also for a host of other diseases, including other viral infections and even cancer. “COVID-19 has brought to the front something that a lot of people have ignored.”

The post How anti-ageing drugs could boost COVID vaccines in older people appeared first on MyMedicPlus.

Jules Renard, the French author, said, “It is not a question of how old you are, but a question of how you are old.” We cannot control aging but how do we prevent it before time? Before we delve into understanding how preventive healthcare is the new form of anti-aging, let’s try to comprehend what causes us to age.

A study published on NCBI by Stefan Liochev, a scholar from Duke University Medical Centre in the United States, states “The causes of aging synergize with each other”. The study also states that aging is a result of damage to cells, tissues, and organs that leads to the development of pathological conditions and eventually, death. According to Medical News Today, the damage is a result of several factors like environmental, psychological, poor diet, stress, etc.

Johnny Bowden, the nutritionist, and best-selling author told U.S. News that only 5–10% of our aging process is related to our genes. The rest is how we treat our bodies. He states that four causes of aging are dependent on free radicals, inflammation, stress, and too much sugar.

But how do we determine things like the level of inflammation or the amount of sugar in our bodies? It’s possible through preventive healthcare. Cheaper than curative healthcare, preventive healthcare allows knowing what is going on with our bodies. For example, too much sugar shows up in blood tests while stress tests determine whether an individual is too stressed. Vitamin and mineral deficiencies play a huge role in determining the functioning of our bodies can also help prevent some diseases, or get them diagnosed in the nascent stage.

Aging leads to diseases. Diseases lead to death. Preventive healthcare can slow down the aging of the cells. Aging doesn’t necessarily mean an increase in the number of years you have lived. It also means the age of your body and how healthy your body is. Two people who are 30 years old may have a different body age and different fitness levels. Death happens after the biological aging of the body. But through preventive healthcare, it can be slowed to the normal pace, reducing the number of preventable deaths in the world.

Preventive healthcare spans across tests, screenings, regular checkups, lifestyle changes, immunizations, counselling, etc. This includes not only the physiological aspects but also the psychological ones as stress is one of the leading causes of aging. It analyzes what influences a person’s health through biostatistics and epidemiology.

Even the smallest change in your body (biological aging) can show up in the preventive medical tests. This enables the diagnosis and treatment of several aging-related diseases like cancer and ultimately contributes to having a longer lifespan and enhancing the quality of life.

The best hack for anti-aging is preventive healthcare. Know what’s going on with your body and treat it before it overpowers your bodily functions. Stay one step ahead!

“This article is exclusively produced for The Times of India Healthy India, Fit India initiative by our partner, Healthians to spread awareness on the importance of preventive health care”

The post Preventive Healthcare: New form of anti-ageing appeared first on MyMedicPlus.

A popular diabetes drug sometimes taken to slow ageing may diminish some of the expected health benefits of aerobic exercise in healthy older adults, according to a new report. The drug, metformin, can blunt certain physical changes from exercise that normally help people to age well.

The results raise questions about the relationship of pills and physical activity in healthy ageing and also whether we know enough about how drugs and exercise interact. The results are particularly disconcerting given that healthy, active people may be considering taking the drug to slow ageing.

Metformin currently is the most-prescribed medication globally for people with type 2 diabetes. It allows people with type 2 diabetes to improve their blood-sugar control and insulin sensitivity, in large part by reducing the amount of sugar released by the liver into the blood. In people with diabetes, the benefits can clearly outweigh the risks.

But in recent years, scientists, physicians and plenty of other people entering middle age have become intrigued by the idea that it might also change how healthy people age. Worms and rodents given metformin typically outlive their unmedicated labmates. These animal studies suggest the drug not only reduces blood sugar, it also reduces inflammation and produces other cellular effects that alter aging.

Exercise also influences ageing, of course. Animal and human studies show, for example, that regular activity raises people’s aerobic fitness and increases their insulin sensitivity, both of which are linked with longer, healthier life spans.

Greater anti-ageing benefits

Unsurprisingly, some researchers have speculated that combining metformin and exercise might lead to even greater anti-ageing benefits than either approach alone. But little has been known about just how and whether metformin and exercise might work together deep inside our bodies and cells.

So, for the new study, which was published in Aging Cell, researchers at the Oklahoma Medical Research Foundation, Colorado State University and the University of Illinois decided to ask healthy people to sweat and swallow metformin. They began by recruiting 53 sedentary but otherwise healthy men and women in their early 60s. Most had risk factors for type 2 diabetes, such as a family history, but were not diabetic.

The researchers measured the volunteers’ current aerobic fitness, blood-sugar levels, insulin sensitivity and body mass. They also took tiny leg-muscle biopsies and randomly assigned the volunteers to start taking either metformin or a placebo. All of the volunteers then began a supervised exercise programme, visiting the lab three times a week to jog on a treadmill or pedal a bike for 45 minutes, a routine that lasted for four months.

Afterwards, the researchers repeated all of the measurements from the study’s start and compared the two groups.

It turned out, to no one’s surprise, that most of the volunteers now had better aerobic fitness and blood-sugar control than before, as well as improved insulin sensitivity. Each of these physiological changes would be expected to improve how well the volunteers aged.

But there were notable disparities between the two groups.

Overall, the men and women taking metformin gained less fitness, upping their endurance by about half as much as those swallowing the placebo. Many of those taking the drug also showed slighter, if any, improvements in insulin sensitivity. (Hardly anyone’s weight changed much, in either group.)

The scientists next looked microscopically inside their volunteers’ muscles and found telling discrepancies between the two groups. The muscle cells of the exercisers on placebo teemed with active mitochondria, which are the cells’ powerhouses. Mitochondria transform oxygen and sugar into cellular fuel in a process referred to as mitochondrial respiration. Higher respiration generally means better cellular health.

In the muscle cells from the men and women on placebo, mitochondrial respiration rose by about 25 per cent, compared to levels at the study’s start. But not so in the muscle cells from the metformin group, which showed little if any upswing in mitochondrial respiration.

Road-blocked

In effect, metformin had road-blocked the normal exercise-related gains in muscle-cell mitochondrial respiration, says Benjamin Miller, a principal investigator in the ageing and metabolism research programme at the Oklahoma Medical Research Foundation, who oversaw the study.

Without these souped-up mitochondria, the exercisers on metformin seemed less able to improve their fitness or insulin sensitivity than the other volunteers.

These results do not mean that people should stop or avoid using metformin, Miller cautions, even to brake ageing. The study followed only a small group of people for a relatively short period of time and examined a mere fraction of the voluminous bodily effects of exercise and metformin. It also did not include people taking metformin without exercise.

But the findings “do give us reason to think a bit more cautiously” about mixing metformin and exercise in healthy people, Miller says. “There was not an additive effect” from combining them, he says. Instead, metformin and exercise “did not seem to play together very well”.

More research is needed, though, to understand how metformin affects mitochondria, exercise and ageing, he says. More broadly, the results raise questions about how exercise might respond to other medicines. “Doctors are very cognisant of drug-drug interactions,” he says. “It’s time we consider drug-and-exercise interactions, too.” – New York Times

The post A bitter pill: anti-ageing drug halts health benefits of exercise appeared first on MyMedicPlus.

The global anti-ageing market is worth at least $250 billion – an astonishing amount, and it’s growing. Anti-ageing treatments are supposedly used to correct “premature ageing”. But what does this really mean? Surely, ageing is just ageing. It is a process that occurs over time – at the time that it’s supposed to.

The target consumer, and so audience for this narrative of accelerated ageing, is overwhelmingly women – unsurprisingly. Men and women age roughly at similar speeds, but the language and pictures around anti-ageing treatments suggest that women have far and away the most to worry about. Any online search will reveal a standard picture of a young woman scrutinising her reflection and hastily applying cream to her face.

The message is clear: it’s a race against time. Many companies advise women to start using these treatments in their 20s. Men worry about ageing too, but advice for their skin is packaged as maintenance rather than emergency.

This focus on the ageing of women is by no means a modern phenomenon. We can, in part, blame the Victorians. The Victorians judged age by appearance more than by chronology – especially as the ill-educated were not likely to know their age, or the age of their relatives. They also believed, or at least encouraged the belief, that women were more delicate than men. They thought that a woman’s body was in many ways the opposite to a man’s and that women were physically and emotionally weaker too.

People have always been interested in the ageing process and how to stop it, but it was only in the 19th century that ageing was seriously studied. The mid-Victorian period saw the rise of gerontology: the study of ageing.

Victorian gerontology

The Victorians made progress with thinking about elderly people and what they need to survive. They established that older patients required different food and noted that the largest proportion of older people die in the winter.

But there were some more curious claims being made about ageing, too. The first gerontologist, George Edward Day, made some particularly odd claims about women. He believed that women enter old age faster and continue to age ahead of men. As a man, perhaps it was tempting to see ageing as something that happened faster to the other sex.

Victorian physicians were influenced by classical thinking. Hippocrates and Aristotle both argued that women aged faster than men. Despite Day’s progressive view that old people were worth specialist care, Day still theorised that women were in the process of declining into old age by around 40. Men, on the other hand, supposedly didn’t show signs of ageing until they were around 48 or 50. Day stated that, in the race to the grave, women were at best biologically five years older than a man of the same age and at worst ten years older.

Now, of course, we know this isn’t true. But it is a narrative that hasn’t really disappeared – as the enormous market for anti-ageing products aimed at women reveals.

Victorian novels

The assumption that men and women are biologically dissimilar and experience age differently was promoted in Victorian fiction too. Authors including Charles Dickens, Henry James and H Rider Haggard seemed to delight in embellishing the details of female decrepitude. And, in much of their fiction, ageing women seem to be at fault for declining in the way they do. It’s worth thinking about how these aspects of ageing still niggle away at women today.

Henry James’s Juliana Bordereau is depicted as a living corpse, whose grip on life equates to temerity, especially as she was once a beauty. Dickens’s Miss Havisham, meanwhile, crumbles into an old hag because of the bitterness of marital rejection. His poisonous Mrs Skewton cannot hide her hideous interior, or exterior – even when she is caked with cosmetics. Yet the author insists that she looks even worse without make-up.

Most pertinently, H Rider Haggard’s novel Ayesha makes it clear that his heroine Ayesha is up to something. Even as the narrator is attracted to her body, he senses something deathly around her person. This is because Ayesha is more than 2000 years old. She still looks beautiful because she has found the elixir of youth in the form of a fire. There is little doubt that using such a substance is morally wrong, since Ayesha is punished for it. By overdoing the treatment, Ayesha dies, covered in a million wrinkles.

Echoes of all of these sorry tales are seen in the puzzling narrative of today’s anti-ageing culture. If a woman makes no attempt to maintain her looks – or to hide the effects of ageing – she has failed. If, on the other hand, she succumbs to temptation and tries to cheat the ageing process, she may end up damaging her face – through plastic surgery or otherwise. Female celebrities who maintain their looks are scrutinised in the media, with the view that if we watch them long enough, they will surely begin to disintegrate. Who would have thought that we could blame the Victorians for this dilemma?

The post The Victorians believed that women aged faster than men – a myth that persists today appeared first on MyMedicPlus.