For older patients in intensive care units (ICUs), COVID is more severe than bacterial or viral pneumonia, suggests new research published in the Journal of the American Geriatrics Society.
Among 11 525 patients aged 70 years and older who were admitted to Dutch ICUs, ICU-mortality and hospital-mortality rates of patients admitted with COVID were 39.7% and 47.6%, respectively. These rates were higher than the mortality of patients admitted because of pneumonia from causes other than COVID. (ICU- and hospital-mortality rates of patients admitted with bacterial pneumonia were 19.1% and 28.8%, respectively, and with viral pneumonia were 22.7% and 31.8%, respectively). Differences persisted after adjusting for several clinical characteristics and intensive care unit occupancy rate.
“In ICU-patients aged 70 years and older, COVID is more severe – with approximately double mortality rates – compared with bacterial or viral pneumonia. Nevertheless, more than half of these older patients admitted to Dutch ICUs with COVID survived the hospital,” said corresponding author Lenneke E. M. Haas, MD, PhD, of Diakonessenhuis, in the Netherlands. “Our findings provide important additional data to include in informed goals-of-care discussions.”
New research published in the Journal of the American Geriatrics Society reports that motor vehicle collisions decreased after Japan implemented a mandatory cognitive screening test for older drivers when they renewed their drivers’ licences. For older pedestrians and cyclists, however, their number of collisions and injuries increased.
For the study, investigators analysed police-reported data on the number of collisions for drivers and injuries for pedestrians and cyclists among people aged 70 years or older in Japan from July 2012 to December 2019. As of March 2017, drivers aged 75 years or older who screen positive are required to see a physician before license renewal. If diagnosed with dementia, their licenses may be suspended or revoked.
From 2012 to 2019, there were 602 885 collisions for drivers and 196 889 injuries for pedestrians and cyclists among people aged 70 years or older. After the 2017 policy, collisions decreased among male drivers, and injuries increased among some age subgroups in both sexes. Cumulative estimated changes in the numbers of collisions and injuries from March 2017 to December 2019 were -3670 and 959, respectively.
“Safety measures need to be strengthened for older cyclists and pedestrians. We should also provide older people with necessary care to prepare for driving cessation and safe, alternative transport means,” said corresponding author Haruhiko Inada, PhD, a post-doctoral fellow at the Johns Hopkins Bloomberg School of Public Health.
Studies over the past several years have shown that infusions of young blood seem to produce a rejuvenating effect when infused into older bodies. Ageing hearts beat stronger, muscles become stronger, and thinking becomes sharper.
While some scientists have considered trying to replicate this effect with a pill, others have focused on rejuvenating the haematopoietic stem cells that actually make the blood – something which may be possible, based on recent findings from a study published in Nature Cell Biology.
“An ageing blood system, because it’s a vector for a lot of proteins, cytokines, and cells, has a lot of bad consequences for the organism,” says Emmanuelle Passegué, PhD, director of the Columbia Stem Cell Initiative, who’s been studying how blood changes with age. “A 70-year-old with a 40-year-old blood system could have a longer healthspan, if not a longer lifespan.”
Passegué, with her graduate student Carl Mitchell, found that an anti-inflammatory drug, already approved for use in rheumatoid arthritis, can turn back time in mice and reverse some of the effects of age on the hematopoietic system.
“These results indicate that such strategies hold promise for maintaining healthier blood production in the elderly,” Mitchell says.
Returning blood stem cells to a younger state
The researchers only identified the drug after a investigation of stem cells for blood and the niches where they reside in the centre of the bones.
All blood cells in the body are created by a small number of stem cells that reside in bone marrow. Over time, these haematopoietic stem cells start to change, producing fewer red blood cells (leading to anaemia) and fewer immune cells (which raises the risk of infection and impedes vaccination efforts), and they have trouble maintaining the integrity of their genomes (which can lead to blood cancers).
In a 2021 Journal of Experimental Medicine paper, Passegué and her team first tried to rejuvenate old haematopoietic stem cells in mice, with exercise or a calorie-restricted diet, both generally thought to slow the ageing process. Both failed, as did transplanting old stem cells into young bone marrow. Even young blood had no effect on rejuvenating old blood stem cells.
Mitchell and Passegué then took a closer look at the stem cells’ environment, the bone marrow. “Blood stem cells live in a niche; we thought what happens in this specialised local environment could be a big part of the problem,” Mitchell says.
With techniques developed in the Passegué lab that enable detailed investigation of the bone marrow milieu, the researchers found that the ageing niche is deteriorating and overwhelmed with inflammation, leading to dysfunction in the blood stem cells.
One inflammatory signal released from the damaged bone marrow niche, IL-1B, was critical in driving these ageing features, and blocking it with the drug, anakinra, remarkably returned the blood stem cells to a younger, healthier state.
Even more youthful effects on both the niche and the blood system occurred when IL-1B was prevented from exerting its inflammatory effects throughout the animal’s life.
The researchers are now trying to learn if the same processes are active in humans and if rejuvenating the stem cell niche earlier in life, in middle age, would be a more effective strategy.
Meanwhile, “treating elderly patients with anti-inflammatory drugs blocking IL-1B function should help with maintaining healthier blood production,” Passegué says, and she hopes the finding will lead to clinical testing.
“We know that bone tissue begins to degrade when people are in their 50s. What happens in middle age? Why does the niche fail first?” Passegué says. “Only by having a deep molecular understanding will it be possible to identify approaches that can truly delay ageing.”
Many societies have added more than 30 years to life expectancy in the past century. “Now it is imperative to conduct the science to determine how to create health and well-being across the full length of those lives,” says Linda Fried, MD, MPH, dean of the Mailman School of Public Health at Columbia University and director of the Butler Columbia Aging Center. “This must include research to understand the mechanisms of normal aging and how to fully develop the huge opportunities to create healthy longevity for all.”
In a new study published in the journal Science, researchers exploring circadian molecular rhythms were able to uncover the organisation of gene expression rhythms in particular human tissues, and found that sex and age are involved, with females having a more regular pattern of rhythms.
In model organisms, analysing molecular rhythms is usually done using time-stamped measurements, but such data are not readily available in humans. To work around this, the researchers used existing measurements from a large cohort of post-mortem donors, combined with a novel computer algorithm that was designed to assign internal clock times to nearly one thousand donors.
“Interestingly, the data-science algorithm we developed turned out to resemble models from magnetic systems, which are well studied in statistical physics,” says study leader Felix Naef at Ecole Polytechnique Fédérale de Lausanne. Using this innovative approach, the researchers obtained the first comprehensive and accurate whole-organism view of 24-hour gene expression rhythms in 46 human tissues.
While the core clock machinery properties are conserved across the body and do not change significantly with sex and age, their analysis also revealed extensive programs of gene expression rhythms across major compartments of metabolism, stress response pathways and immune function, and these programs peaked twice a day.
In fact, the emerging whole-body organisation of circadian timing shows that rhythmic gene expression occurs as morning and evening waves, with the timing in the adrenal gland peaking first, while brain regions displayed much lower rhythmicity compared to metabolic tissues.
Dividing the donors by sex and age revealed a previously unknown richness of sex- and age- specific gene expression rhythms spread across biological functions. Strikingly, gene expression rhythms were sex-dimorphic (different in males and females) and more sustained in females, while rhythmic programs were generally reduced with age across the body.
Sex-dimorphic rhythms were particularly noticeable in the liver’s “xenobiotic detoxification,” the process by which liver breaks down harmful substances. Additionally, the study found that with age, the rhythm of gene expression decreases in the heart’s arteries, which may explain why older people are more susceptible to heart disease. This information could be useful in the field of “chronopharmacology,” which is the study of how a person’s internal clock affects the effectiveness and side effects of medication.
This study provides new insights into the complex interplay between our body clock, sex, and age. By understanding these rhythms, we might find new ways of diagnosing and treating pathologies such as sleep disorders and metabolic diseases.
The University of California San Diego-led team reported that among women aged 65 or older, each extra 31 minutes per day of moderate-to-vigorous physical activity was linked to a 21% lower risk of developing mild cognitive impairment or dementia. Risk was also reduced by 33% with each extra 1865 daily steps.
“Given that the onset of dementia begins 20 years or more before symptoms show, the early intervention for delaying or preventing cognitive decline and dementia among older adults is essential,” said senior author Andrea LaCroix, PhD, MPH, UC San Diego professor.
Dementias are a debilitating neurological condition that can cause loss of memory, the ability to think, problem solve or reason. Mild cognitive impairment is an early stage of memory loss or thinking problems that is not as severe as dementias.
More women live with and are at higher risk of developing dementia than men.
“Physical activity has been identified as one of the three most promising ways to reduce risk of dementia and Alzheimer’s disease. Prevention is important because once dementia is diagnosed, it is very difficult to slow or reverse. There is no cure,” said LaCroix.
However, because few large studies have examined device measures of movement and sitting in relation to mild cognitive impairment and dementia, much of the published research on the associations of physical activity and sedentary behavior with cognitive decline and dementia is based on self-reported measures, said first author, Steven Nguyen, Ph.D., M.P.H., postdoctoral scholar at the Herbert Wertheim School of Public Health.
For this study, the researchers sampled data from 1,277 women as part of two Women’s Health Initiative (WHI) ancillary studies – the WHI Memory Study (WHIMS) and the Objective Physical Activity and Cardiovascular Health (OPACH) study. The women wore research-grade accelerometers and went about their daily activities for up to seven days to obtain accurate measures of physical activity and sitting.
The activity trackers showed the women averaged 3,216 steps, 276 minutes in light physical activities, 45.5 minutes of moderate-to-vigorous physical activity and 10.5 hours of sitting per day. Examples of light physical activity could include housework, gardening or walking. Moderate-to-vigorous physical activity could include brisk walking.
The study findings also showed that higher amounts of sitting and prolonged sitting were not associated with higher risk of mild cognitive impairment or dementia.
Together, this information has clinical and public health importance as there is little published information on the amount and intensity of physical activity needed for a lower dementia risk, said Nguyen.
“Older adults can be encouraged to increase movement of at least moderate intensity and take more steps each day for a lower risk of mild cognitive impairment and dementia,” said Nguyen.
“The findings for steps per day are particularly noteworthy because steps are recorded by a variety of wearable devices increasingly worn by individuals and could be readily adopted.”
The authors said further research is needed among large diverse populations that include men.
Researchers have found that, in animal studies, the hypertension drug rilmenidine can extend lifespan and slow ageing. Published in Aging Cell, the findings show that animals treated with rilmenidine at young and older ages increases lifespan and improves health markers by mimicking the effects of caloric restriction.
They also demonstrate that the healthspan and lifespan benefits of rilmenidine treatment in the roundworm C. elegans are mediated by the I1-imidazoline receptor nish-1, identifying this receptor as a potential longevity target.
With side-effects being rare and non-severe, unlike other drugs previously studied for this purpose by the researchers, the widely-prescribed antihypertensive has potential for future translatability.
A caloric restriction diet has thus far proved to be the most robust anti-ageing intervention, promoting longevity across species. However, studies of caloric restriction in humans have had mixed results and side effects, meaning finding medications like rilmenidine that can mimic the benefits of caloric restriction is the most reasonable anti-ageing strategy.
Professor João Pedro Magalhães, who led the research whilst at the University of Liverpool and is now based at the University of Birmingham, said: “With a global ageing population, the benefits of delaying ageing, even if slightly, are immense. Repurposing drugs capable of extending lifespan and healthspan has a huge untapped potential in translational geroscience. For the first time, we have been able to show in animals that rilmenidine can increase lifespan. We are now keen to explore if rilmenidine may have other clinical applications.”
To date, it has been assumed that bones lack lymphatic vessels, but new research published in the journal Cell not only mapped them within bone tissue, but demonstrated their role in bone and blood cell regeneration and reveals changes associated with ageing.
The network of vessels that form the lymphatic system plays an important role in draining excess fluid from tissues, clearing waste products and supporting immune responses.
The fine network of lymph vessels extends throughout the body, but a small number of sites such as the brain, eye and bone were previously assumed to lack lymph tissue. The hard tissue of bone in particular has traditionally made studying the distribution and role of blood and lymph more difficult.
Researchers used light-sheet imaging to identify and visualise the lymphatic vessels of bone in high-resolution 3D, revealing an active network of lymph vessels within bone. The researchers further identified some of the key signals happening between lymph vessels, blood stem cells and bone stem cells.
Dr Lincoln Biswas, co-first author of this study, said: ‘Interestingly after injury, lymphatic vessels in bone show dynamic crosstalk with blood stem cells and with specialised perivascular cells in order to accelerate bone healing. Such interactions between lymphatics and bone stem cells can harnessed to promote bone healing such as in fracture repair.’
The researchers found that lymphatic vessels in bone increase during injury via a signalling molecule called IL6, and trigger expansion of bone progenitor cells by secreting a different signal, called CXCL12. Dr Junyu Chen, a co-first author of the study now based at Sichuan University said: “Ageing is associated with diminished capacity for bone repair, and our findings show that lymphatic signalling is impaired in aged bones. Remarkably, the administration of young lymphatic endothelial cells restores healing of aged bones, thus providing a future direction to promote bone healing in elderly.”
Dr Anjali Kusumbe, who led the research said: “I am very excited as these findings not only demonstrate that lymphatic vessels do exist in bone but also reveal their critical interactions with blood stem cells and perivascular bone stem cells after injury to promote healing, thereby presenting lymphatics as a therapeutic avenue to stimulate bone and blood regeneration. Further, these findings are very fundamental, opening doors for understanding the impact of bone lymphatics on the immune system and their role in bone and blood diseases.”
An international study demonstrates for the first time that degradation in epigenetic information can drive ageing in an organism, independently of changes to the genetic code itself. Published in the journal Cell, the work shows that a breakdown in epigenetic information causes mice to age and that restoring the integrity of the epigenome reverses those signs of ageing.
“We believe ours is the first study to show epigenetic change as a primary driver of ageing in mammals,” said the paper’s senior author, David Sinclair, professor of genetics at Harvard Medical School.
The team’s extensive series of experiments provide long-awaited confirmation that DNA changes are not the only, or even the main, cause of ageing. Rather, the findings show, chemical and structural changes to chromatin contribute ageing without changing the genome.
“We expect the findings will transform the way we view the process of ageing and the way we approach the treatment of diseases associated with ageing,” said co-first author Jae-Hyun Yang, research fellow in genetics in the Sinclair lab.
Since it is easier to manipulate epigenetics than DNA, this could lead to a whole new avenue of research. Studies in nonhuman primates are currently underway.
“We hope these results are seen as a turning point in our ability to control aging,” said Sinclair. “This is the first study showing that we can have precise control of the biological age of a complex animal; that we can drive it forwards and backwards at will.”
Beyond mutations
A reigning, decades-old theory of ageing was that it arises from an accumulation of changes to DNA, primarily genetic mutations, which over time prevent more and more genes from functioning properly. Over time, researchers began finding contradictory evidence: in some human and mice, high mutation rates was not accompanied by premature ageing, while many types of aged cells lacked mutations. Some researchers believed that epigenetics could be the true culprit.
A component of epigenetics is the physical structures such as histones that bundle DNA into tightly compacted chromatin and unspool portions of that DNA when needed. Bundled up, genes are inaccessible when but are available to be copied and used to produce proteins when they’re unspooled. Thus, epigenetic factors regulate which genes are active or inactive in any given cell at any given time.
By acting as a toggle for gene activity, these epigenetic molecules help define cell type and function. Since each cell in an organism has basically the same DNA, it’s the on-off switching of particular genes that differentiates a nerve cell from a muscle cell from a lung cell.
“Epigenetics is like a cell’s operating system, telling it how to use the same genetic material differently,” said Yang, who is co-first author with Motoshi Hayano, a former postdoctoral fellow in the Sinclair lab who is now at Keio University School of Medicine in Tokyo.
In the late 1990s and early 2000s, Sinclair’s lab and others showed in yeast and mammals that epigenetic changes were associated with ageing but could not determine whether they caused it or were caused by it. At least, this new study let the scientists disentangle epigenetic causes from genetics.
ICE mice
The team’s main experiment involved creating temporary, fast-healing cuts in the DNA of lab mice, which mimicked those breaks chromosomes that mammalian cells receive on a daily basis from things like breathing, exposure to sunlight and cosmic rays, and contact with certain chemicals. This let the researchers simulate a sped-up life.
Most of the breaks did not happen in the DNA’s coding regions, so did not cause mutations. Rather, the breaks altered the way DNA is folded.
Sinclair and colleagues called their system ICE, short for inducible changes to the epigenome.
At first, epigenetic factors paused their normal job of regulating genes and moved to the DNA breaks to coordinate repairs. Afterward, the factors returned to their original locations.
But as time passed, things changed. The researchers noticed that these factors got ‘distracted’ and did not return home after repairing breaks. The epigenome grew disorganised and began to lose its original information. Chromatin got condensed and unspooled in the wrong patterns, a hallmark of epigenetic malfunction.
As the mice lost their youthful epigenetic function, they began to look and act old. The researchers saw a rise in biomarkers that indicate ageing. Cells lost their identities as, for example, muscle or skin cells. Tissue function faltered. Organs failed.
The team used a tool recently developed by Sinclair’s lab to measure how biologically old the mice were, based on how many sites across the genome lost the methyl groupsnormally attached to them. Compared to untreated mice born at the same time, the ICE mice had aged significantly more.
Young again
Next, the researchers gave the mice a gene therapy that reversed the epigenetic changes they’d caused, which Sinclair likened to rebooting a malfunctioning computer.
The therapy delivered a trio of genes (Oct4, Sox2, and Klf4, together named OSK) that are active in stem cells and can help rewind mature cells to an earlier state. (Sinclair’s lab used OSK to restore sight in blind mice in 2020.)
The ICE mice’s organs and tissues resumed a youthful state.
The therapy “set in motion an epigenetic program that led cells to restore the epigenetic information they had when they were young,” said Sinclair. “It’s a permanent reset.”
How exactly OSK treatment achieved that remains unclear.
At this stage, Sinclair says the discovery supports the hypothesis that mammalian cells maintain a kind of backup copy of epigenetic software that, when accessed, can allow an aged, epigenetically scrambled cell to reboot into a youthful, healthy state.
For now, the extensive experiments led the team to conclude that “by manipulating the epigenome, aging can be driven forwards and backwards,” said Yang.
From here
The ICE method offers researchers a new way to explore the role of epigenetics in ageing and other biological processes.
Because signs of ageing developed in the ICE mice after only six months rather than toward the end of the average mouse life span of two and a half years, the approach also saves time and money for researchers studying aging.
Yang said that researchers can also look beyond OSK gene therapy to other methods such as drugs, to determine how lost epigenetic information might be restored in aged organisms.
Watch the team describe their research in the video below.
Hypertension and diabetes are known risk factors for stroke, but now a new study shows that the amount of risk may decrease as people age. The study is published in Neurology.
“High blood pressure and diabetes are two important risk factors for stroke that can be managed by medication, decreasing a person’s risk,” said study author George Howard, DrPH, of the University of Alabama at Birmingham School of Public Health. “Our findings show that their association with stroke risk may be substantially less at older ages, yet other risk factors do not change with age. These differences in risk factors imply that determining whether a person is at high risk for stroke may differ depending on their age.”
The study involved 28 235 people who had never had a stroke and were followed for 11 years. Risk factors included hypertension, diabetes, smoking, atrial fibrillation, heart disease and left ventricular hypertrophy. Because of the well-known higher stroke risk in Black people (comprising 41% of participants), race was also considered as part of the assessed risk factors, Howard added.
Researchers followed up with participants every six months, confirming strokes by reviewing medical records.
During the study, there were 1405 strokes over 276 074 person-years. Participants were divided into three age groups. The age ranges for those groups varied slightly depending on the data being analysed by researchers. In general, the younger group included participants ages 45–69, the middle group included people in their late 60s to 70s and the older group included people 74 and older.
Researchers found that people with diabetes in the younger age group were approximately twice as likely to have a stroke as people of similar age who did not have diabetes, while people with diabetes in the older age group had an approximately 30% higher risk of having a stroke than people of similar older age who did not have diabetes.
Researchers also found that people with high blood pressure in the younger age group had an 80% higher risk of having stroke than people of similar age without high blood pressure while that risk went down to 50% for people with high blood pressure in the older age group compared to people of similar age without high blood pressure.
With race/ethnicity as a risk factor, Black participants in the younger age group compared to White participants in that group, a difference which decreased in the older age group. For stroke risk factors such as smoking, atrial fibrillation and left ventricular hypertrophy, researchers did not find an age-related change in risk.
“It is important to note that our results do not suggest that treatment of high blood pressure and diabetes becomes unimportant in older age,” said Howard. “Such treatments are still very important for a person’s health. But it also may be wise for doctors to focus on managing risk factors such as atrial fibrillation, smoking and left ventricular hypertrophy as people age.”
Howard also noted that even where the impact of risk factors decreases with age, the total number of people with strokes at older ages may still be larger since overall risk of stroke increases with age. For example, in the younger age group for hypertension, researchers estimate that about 2.0% of normotensive people had a stroke, compared to 3.6% of hypertensive people. In the older age group, about 6.2% of normotensive people had a stroke, compared to 9.3% of hypertensive people.
A limitation of the research was that participants’ risk factors were assessed only once at the start of the study, and it’s possible they may have changed over time.
Hormone Replacement Therapy (HRT) could help prevent Alzheimer’s Dementia among women at risk of developing the disease, according to a study published in Alzheimer’s Research and Therapy.
The research team found that HRT was most effective when introduced early in the menopause journey during perimenopause.
Prof Anne-Marie Minihane, from University of East Anglia, led the study in collaboration with Prof Craig Ritchie at the University of Edinburgh.
Prof Minihane said: “We know that 25% of women in the UK are carriers of the APOE4 gene and that almost two thirds of Alzheimer’s patients are women.
“In addition to living longer, the reason behind the higher female prevalence is thought to be related to the effects of menopause and the impact of the APOE4 genetic risk factor being greater in women.
“We wanted to find out whether HRT could prevent cognitive decline in at-risk APOE4 carriers.”
The research team studied data from 1178 women participating in the European Prevention of Alzheimer’s Dementia initiative, a study set up to record participants’ brain health over time.
The project spanned 10 countries and tracked participants’ brains from ‘healthy’ to a diagnosis of dementia in some. Participants were included if they were over 50 and dementia-free.
The research team studied their results to analyse the impact of HRT on women carrying the APOE4 genotype.
Dr Rasha Saleh, also from UEA’s Norwich Medical School, said: “We found that HRT use is associated with better memory and larger brain volumes among at-risk APOE4 gene carriers. The associations were particularly evident when HRT was introduced early — during the transition to menopause, known as perimenopause.
“This is really important because there have been very limited drug options for Alzheimer’s disease for 20 years and there is an urgent need for new treatments.
“The effects of HRT in this observation study, if confirmed in an intervention trial, would equate to a brain age that is several years younger.”
Prof Anne Marie Minihane said: “Our research looked at associations with cognition and brain volumes using MRI scans. We did not look at dementia cases, but cognitive performance and lower brain volumes are predictive of future dementia risk.”
Prof Michael Hornberger, from UEA’s Norwich Medical School, said: “It’s too early to say for sure that HRT reduces dementia risk in women, but our results highlight the potential importance of HRT and personalised medicine in reducing Alzheimer’s risk.
“The next stage of this research will be to carry out an intervention trial to confirm the impact of starting HRT early on cognition and brain health. It will also be important to analyse which types of HRT are most beneficial,” he added.
