Unlocking The Secrets of Eternal Youth, Enhancing Memory And Intelligence
New research on how we can unlock eternal youth, enhance memory and intelligence could help in understanding and early detection of Alzheimer’s disease and dementia. Unlocking The Secrets of Eternal Youth, Enhancing Memory And Intelligence
Our bodies know when to fall asleep and when to wake up. Our brains can keep track of short bursts of time like a mental stopwatch. But in our memories, our sense of time is fuzzy. Now, research is beginning to uncover how we put our memories in order.
These new insights into the workings of the brain, paired with other findings, could help in the understanding and early detection of diseases such as dementia and Alzheimer’s, scientists say.
The idea that we perceive time in our memory subjectively is well known in psychology, says Lila Davachi, a professor of psychology at Columbia University. People may feel as if a day flies by when it’s busy, but later the memory stretches out because of the large number of recalled details.
Neuroscientists, however, have long had a limited understanding of how the brain marks this sense of time. Most research has pointed to the learning and memory hub of the brain, known as the hippocampus, and the surrounding brain regions. Now neuroscientists are homing in on the lateral entorhinal cortex, or LEC, which feeds into the memory hub, as a more specific time marker for memories.
“It’s not a clock in the way we think of a ticking metronome,” says James Knierim, a professor of neuroscience at Johns Hopkins University and a researcher on a recent study that broke ground in this area. “It’s a signal that changes over time as a result of the experience.”
In the study, published in the journal Nature in September 2018, researchers allowed rats to roam in an open area while recording their brain activity. Each time researchers changed the surroundings by switching the wall color, the LEC area of the rats’ brains responded more than anywhere else. Looking back at those signals, the researchers could create an accurate timeline of events.
When the rats ran laps on a figure-eight track, the same area of the brain marked specific movements, like left or right turns. But the signal was weaker in marking the laps themselves, says Albert Tsao, now a postdoctoral researcher at Stanford and the first author on the study.
These animal findings can potentially be extrapolated to human experiences, says Edvard Moser, a Nobel laureate neuroscientist and senior researcher on the study. Similar to the rats running a figure-eight, if humans have a repetitive schedule, the time marker might start to repeat itself. “You may forget if this happens on a Monday, Tuesday or Wednesday, because the same thing is happening again,” says Dr. Moser, who is co-director of the Kavli Institute for Systems Neuroscience in Norway.
A study published in January in Nature Neuroscience added support to the idea that the LEC plays a role in time and memory. In the study, 19 college students watched an episode of the television show “Curb Your Enthusiasm” while researchers recorded their brain activity. Afterward, the students were presented with images from the episode and asked to recall when they appeared. The most accurate guesses corresponded with the strongest LEC activity, says Michael Yassa, director of the Center for Neurobiology of Learning and Memory at the University of California, Irvine, and senior researcher on the study.
Such results are causing neuroscience research, which has long focused on how the brain understands and remembers space and location, to increasingly focus on time and memory, experts say. “There’s a lot of work left to do,” says Marc Howard, a cognitive neuroscientist at Boston University. “But there’s no question in my mind that we’re going to make rapid progress in understanding time and memory over the next couple of years.”
Many scientists believe that the new findings could bolster research into Alzheimer’s and dementia.
‘We’re going to make rapid progress in understanding time and memory over the next couple of years.’ —Marc Howard, cognitive neuroscientist, Boston University
Several studies on humans have pinpointed the entorhinal cortex—which consists of the LEC and the medial entorhinal cortex, an important part of the brain’s positioning system—as the starting point for the onset of dementia and Alzheimer’s disease. Some of the earliest symptoms for Alzheimer’s are losing track of the passage of time and dates, becoming disoriented, and even a weakening sense of smell—all cognitive processes now linked to that part of the brain.
Studying that region in brains aging typically and brains developing Alzheimer’s could help spot differences in brain development, Dr. Moser says. If researchers can also pinpoint behavioral differences, physicians might be able to screen for early signs of dementia or Alzheimer’s using time-based judgment tasks.
Dr. Yassa and his team recently launched a brain-imaging study in 150 healthy older adults with risk factors for Alzheimer’s disease. The participants, ages 60 to 85, completed a series of cognitive tasks and had their brains imaged. The team will follow up with participants every two years to see if they can link developments in the brain to specific cognitive impairments that could potentially lead to earlier detection, diagnosis or treatment, he says.
The Key To Eternal Youth—Old Mice
Aging mice are important to research on aging people and command a higher price; ‘The Golden Girls’ of Maine live well past 125 human years
Grace and Blanche, two old mice who were second cousins, reached relative fame before dying within months of each other at their home in Bar Harbor, Maine.
Known fondly as the Golden Girls at Jackson Laboratory, a nonprofit that specializes in research and mouse production, the two were believed to be the oldest living mice in the world just before their passing in 2016.
Gary Churchill, a geneticist who does aging research at the lab, was hoping one of them would reach her fifth birthday, a feat unknown to mice. Grace, the eldest, was 4 years and nine months old when she died, roughly the equivalent of 150 human years.
“We have 1,000 more Graces in the pipeline,” says Dr. Churchill. “We’re gunning for five years.”
Aging mice are important to research on aging people, which is a growing field. Scientists put old mice, which are basically ones between the age of 18 and 24 months, in mazes to see how long it takes them to get out—a test of cognitive abilities. They put them on diets to see if cutting calories helps mice live longer (it does) and house them in groups to test theories about the impact of social networks on aging (it’s good). There’s a Core Facility for Aged Rodents at the University of Michigan’s Geriatrics Center.
Worms and fruit flies are also used in aging research but mice and people have more in common. Both are mammals, for instance. Mice are good for other reasons. They have a relatively short lifespan so researchers don’t have to wait forever for them to reach old age. Plus, they don’t take up as much space as rats, which are about 10 times bigger than mice, says Richard Miller, associate director for research at the University of Michigan center.
Dr. Miller, a professor of pathology, is researching ways to slow the aging rate in mice and screening for drugs that extend their healthy lifespan. He has about 5,000 mice at any given time, most born and raised there, including some of the long-lived mutant Snell dwarf strain, such as Yoda, his first mouse to reach age 4.
He was also interested in seeing if mice whose grandparents lived in barns lived longer than mice whose ancestors lived in labs for generations. They did—barn descendants live about 20% longer than lab mice.
One grandson of two mice found in an Idaho barn almost made it to his fourth birthday, which was notable in 2001 when he died. That mouse, known as IdG1-030, remained spry to the end, chewing wood chips and “doing pull-ups near the food hopper at the top of his cage,” according to an obituary Dr. Miller wrote.
Childless, IdG1-030 was survived by 9 half-nieces and nephews and 28 great half-grandnephews and nieces.
Although aged mice are important for research, supply is limited and cost is high. The National Institute on Aging, which has an Aged Rodent Colonies Handbook, provides older mice for projects directly related to aging, but limits researchers to 20 a month, per NIA grant. All mice must be ordered through its online Rodent Ordering System; replacements are offered for animals that arrive dead or die within 48 hours. Those with a “scruffy or unkempt appearance,” which is often normal with aging in mice, won’t be replaced.
Jackson Labs, which has three mice-production facilities and distributes about 3 million mice a year, has shelf-ready mice available for shipment. Elderly mice are more expensive. A 78-week-old female mouse from Jackson costs $307.14 compared with $74.23 for a 25-week-old one. It also offers a just-in-time service, raising mice to a requested age and then delivering them.
Elizabeth Kirby, a neurologist at Ohio State University, made a discovery when she put seven mice in one cage and two mice in another. All of the mice were 15 to 18 months old, “post-retirement age,” she says.
After about three months, she tested their memory by putting them on a table with holes, some of which were escape hatches, and repeating the process every day. The mice who lived in groups seemed to memorize where the escape hatches were and go directly to them. The old couple mice checked every hole.
“It’d be like walking as quickly as possible through each row of a parking lot to look for your car rather than trying to remember where your car actually is and walk to that spot,” said Dr. Kirby. Having a larger social network seems to help keep the brain healthy, she says.
Other mice, albeit genetically altered ones, have come close to five years.
Andrzej Bartke, a research professor at Southern Illinois University School of Medicine in Springfield, won the Methuselah Mouse Prize, awarded by the nonprofit Methuselah Foundation, in 2003 for the oldest ever mouse, a mutant dwarf mouse that died six days short of its fifth birthday.
“He was exceptional. He lived and lived and lived,” says the 79-year-old-Dr. Bartke, who studies how growth hormone influences aging and longevity. He received clips from newspapers in Switzerland and Kazakhstan carrying news of his mouse. Some researchers were so amazed that they wondered if there was a possible mouse mix-up during a move of Dr. Bartke’s lab facilities and that the mouse didn’t live that long. Dr. Bartke knows of no mix up. “I believe to this day it’s the longest mouse life on record,” he says.
Eva Czirr, a senior scientist at Alkahest, a biotech company, studies memory loss in mice as part of her research into neurodegenerative diseases, such as Alzheimer’s. She found that once a mouse reaches the age of 20 months, it experiences cognitive declines, which in mice means they can no longer navigate water mazes very well or perform activities of daily living, like building a good nest. “Mice are critical for aging research in humans,” she says.
While expensive, the contributions of old mice are priceless, say researchers. “The big question we have is: Do animals and people age at different rates?” says Dr. Churchill, of Jackson Laboratory.
Blanche And Grace Provided Clues
Both mice, who were non-mutants, were born the same week and raised in similar conditions. By their fourth birthday, they looked different. Blanche had a curved spine and tattered fur. Grace, whose black coat remained sleek, aged gracefully.
Exercise Improves Cognition Depending On Type And Amount
The effect is much less pronounced in the obese.
Watch your head
Lifestyle choices, such as exercise and diet, are the most powerful anti-aging interventions currently available to us, and they might be the only effective ones. Exercise, in particular, has been proven to slow down various age-related changes .
One of these changes is cognitive decline. It spares virtually no one, and in some people, it grows into devastating dementias, such as the deadly Alzheimer’s disease.
Geroscientists suspect that the reason not all old people become demented is that most die of other causes before age-related dementias can get to them. As life expectancy continues to rise, finding ways to maintain cognitive health becomes extremely important.
Numerous studies have tested the effect of exercise on age-related cognitive decline, mostly with positive results, but there are many confounding variables, such as types of exercise, sex, and BMI (body mass index).
In this new review, which encompasses 44 studies with almost 5000 participants, the authors set out to determine the minimum and optimal amounts of various types of exercise for influencing age-related cognitive decline.
Some Exercise Is Better Than Nothing
The researchers begin with a brief overview of the current literature, noting that most of it still focuses on aerobic exercise, while other types of exercise have been shown to confer cognitive benefits as well – such as resistance training, dancing, and mind-body practices .
In their analysis, the scientists compare various types of exercise using their MET (metabolic equivalent), an established metric of energy expenditure. One MET-minute equals the amount of energy our body consumes during one minute of absolute rest.
Brisk walking and vigorous weight training score at 5 MET, bicycling on flat terrain is equivalent to 9 MET, and running is one of the most energy-consuming activities at 11.5 MET. That means one minute of running uses up to 11.5 MET-mins worth of energy.
When measuring only MET equivalents and not type of exercise, the review shows that there is no minimum amount of exercise below which it does not promote cognition, however slightly. This sits well with the saying (officially endorsed the WHO) that some exercise is better than no exercise.
However, according to the review, the difference is only perceptible at around 700 MET-minutes per week, which is on the smaller side of WHO recommendations (600-1200 MET-minutes per week).
Starting from 1200 MET-minutes per week, however, the effect becomes weaker, although it never plateaus, which led the researchers to conclude that beyond this point, the further benefits of exercise are unproven. This result aligns well with previous research showing that the benefits of exercise might peak at some point and even be reversed by too much exercise.
Obesity Erases The Effect
The differences between various types of exercise were quite significant. Resistance exercise shows a powerful effect, but it peaks at around 400 MET-minutes per week and then rapidly declines as the dose gets higher, producing an inverted U-shape on the chart. Walking and weightlifting had less pronounced effects on cognition than aerobic exercises.
A mix of various aerobic exercises yielded good results, but a balanced combination of resistance training, weightlifting, and other exercise may be better. One previous meta-analysis indeed found that a mix of various types of exercise is most beneficial .
Finally, obesity seems to drastically change the picture. In people who are overweight, exercise improves cognition only slightly up to about 600 MET-minutes, and any further addition of MET-minutes diminishes the effect. Not only is obesity a major driver of aging, it can dampen the effect of exercise.
The researchers add the obvious observation, which can be taken as a warning, that it might be hard for aging people who had previously led sedentary lifestyles to drastically ramp up their exercise capacity to the recommended levels.
This review provides important insights into the effect that exercise can have on age-related cognitive decline, showing us that not all types of exercise are the same, and answering the question of how much exercise someone actually needs to start improving cognition in old age. It also reminds us that exercise is one of the few interventions available today that can put a dent in aging.
 Gallardo-Gómez, D., del Pozo-Cruz, J., Noetel, M., Álvarez-Barbosa, F., Alfonso-Rosa, R. M., & del Pozo Cruz, B. (2022). Optimal Dose and Type of Exercise to Improve Cognitive Function in Older Adults: A Systematic Review and Bayesian Model-Based Network Meta-Analysis of RCTs. Ageing Research Reviews, 101591.
 Shephard, R. J., & Shek, P. N. (1995). Exercise, aging and immune function. International journal of sports medicine, 16(01), 1-6.
 Biazus-Sehn, L. F., Schuch, F. B., Firth, J., & de Souza Stigger, F. (2020). Effects of physical exercise on cognitive function of older adults with mild cognitive impairment: A systematic review and meta-analysis. Archives of Gerontology and Geriatrics, 89, 104048.
 Huang, X., Zhao, X., Li, B., Cai, Y., Zhang, S., Wan, Q., & Yu, F. (2021). Comparative efficacy of various exercise interventions on cognitive function in patients with mild cognitive impairment or dementia: a systematic review and network meta-analysis. Journal of Sport and Health Science.
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