Study finds why many IVF embryos fail to develop

In humans, a fertilized egg is no guarantee of reproductive success. Most embryos stop developing and perish within days of fertilization, usually because they have an abnormal number of chromosomes. Now, researchers at Columbia University Vagelos College of Physicians and Surgeons have found that most of these mistakes are due to spontaneous errors in DNA replication in the earliest phase of cell division.

The findings provide new insights into the basic biology of human reproduction and in the long term could lead to improvements in the success rate of in vitro fertilization (IVF). The study was published online July 19 in the journal Cell.

Challenging task for early embryos

Approximately 24 hours after a human egg is fertilized, the process of cell division begins. During cell division, the entire genome -- 46 chromosomes containing more than 3 billion base pairs of DNA -- must be faithfully duplicated. The duplicate sets of chromosomes must then be separated so that each daughter cell receives a complete set.

In many human embryos created for IVF, something goes wrong and some cells within the embryo have too few or too many chromosomes.

"Duplicating the genome is a challenging task for the early embryo," says study leader Dieter Egli, PhD, the Maimonides Assistant Professor of Developmental Cell Biology (in pediatrics) at Columbia University Vagelos College of Physicians and Surgeons.

Researchers have long theorized that errors occur during the final phase of cell division, when the duplicate sets of chromosomes separate into two identical daughter cells. Most of these failures were attributed to issues with the microtubule spindle, the apparatus that pulls the two sets of chromosomes apart.

But Egli's studies found that chromosomal abnormalities stem from errors that occur much earlier in the process of cell division when the genome's DNA is duplicated. If the DNA is not copied precisely, his studies found, the spindle malfunctions and places the wrong number of chromosomes into each daughter cell. When DNA duplication is abnormal, the spindle does not function normally. "This has largely been overlooked in previous studies -- because why would the embryo allow the integrity of the genome to be compromised when this is such a critical requirement for normal development?" Egli says.

Though the studies were conducted with embryos created in a petri dish -- including from individuals undergoing IVF and egg donors who were not seeking fertility treatment -- the same problems may contribute to the failure of embryos created in natural human reproduction.

Clues to source of DNA errors

The source of DNA copying errors in embryos appears to spring from obstacles within the DNA's double helix. Though the precise reason for these obstacles is not yet known, they cause duplication of the DNA to pause, or even stop, which results in DNA breakage and an abnormal number of chromosomes.

Spontaneous DNA errors can occur as early as the first cycle of cell division in human embryos, the researchers found, as well as in subsequent cell divisions. If too many cells in the early embryo are affected by chromosomal abnormalities, the embryo cannot develop further.

IVF

Most human embryos created for IVF stop developing within days after fertilization. This inefficiency of human development is an obstacle to successful fertility treatments.

"Many women undergoing fertility treatment require multiple IVF cycles in order to get pregnant, and some never get pregnant at all. Not only is this enormously expensive, it's emotionally taxing," says Jenna Turocy, MD, a fertility specialist at Columbia University Fertility Center and a co-author of the study.

The researchers are planning additional studies looking at DNA damage during replication in the hope of understanding normal and disease-causing variations in the human germ line. In the long term, these studies may lead to methods to reduce the risk of genetic abnormalities and embryo attrition for patients undergoing IVF.

More information

The study is titled, "Replication stress impairs chromosome segregation and preimplantation development in human embryos."

The other contributors (all Columbia unless noted) are: Katherine L. PalmerolaSelma Amrane, Alejandro De Los Angeles, Shuangyi Xu, Ning Wang, Joao de Pinho, Michael V. Zuccaro, Angelo Taglialatela, Dashiell J. Massey (Columbia and Cornell University), Alex Robles, Anisa Subbiah, Bob Prosser, Rogerio Lobo, Alberto Ciccia, Amnon Koren (Cornell), and Timour Baslan (Memorial Sloan Kettering Cancer Center).

This research was supported by a NYSCF-Robertson Stem Cell Investigator award and grants from the United States-Israel Binational Science Foundation, Columbia Stem Cell Initiative, the American Society for Reproductive Medicine, the John M. Driscoll Jr. Children's Fund Scholarship, and by the Russell Berrie Foundation Program in Cellular Therapies.

Dieter Egli is a member of the Cell editorial board.

Journal Reference:

1. Katherine L. Palmerola, Selma Amrane, Alejandro De Los Angeles, Shuangyi Xu, Ning Wang, Joao de Pinho, Michael V. Zuccaro, Angelo Taglialatela, Dashiell J. Massey, Jenna Turocy, Alex Robles, Anisa Subbiah, Bob Prosser, Rogerio Lobo, Alberto Ciccia, Amnon Koren, Timour Baslan, Dieter Egli. Replication stress impairs chromosome segregation and preimplantation development in human embryos. Cell, 2022; DOI: 10.1016/j.cell.2022.06.028 

Courtesy:

Columbia University Irving Medical Center. "Study finds why many IVF embryos fail to develop." ScienceDaily. ScienceDaily, 19 July 2022. <www.sciencedaily.com/releases/2022/07/220719130213.htm>.

 

 

Vitamin B6 supplements could reduce anxiety and depression

Taking high-dose Vitamin B6 tablets has been shown to reduce feelings of anxiety and depression by new research.

Scientists at the University of Reading measured the impact of high doses of Vitamin B6 on young adults and found that they reported feeling less anxious and depressed after taking the supplements every day for a month.

The study, published in the journal Human Psychopharmacology: Clinical and Experimental, provides valuable evidence to support the use of supplements thought to modify levels of activity in the brain for preventing or treating mood disorders.

Dr David Field, lead author from the School of Psychology and Clinical Language Sciences at the University of Reading, said: "The functioning of the brain relies on a delicate balance between the excitatory neurons that carry information around and inhibitory ones, which prevent runaway activity.

"Recent theories have connected mood disorders and some other neuropsychiatric conditions with a disturbance of this balance, often in the direction of raised levels of brain activity.

"Vitamin B6 helps the body produce a specific chemical messenger that inhibits impulses in the brain, and our study links this calming effect with reduced anxiety among the participants."

While previous studies have produced evidence that multivitamins or marmite can reduce stress levels, few studies have been carried out into which particular vitamins contained within them drive this effect.

The new study focused on the potential role of Vitamins B6, which is known to increase the body's production of GABA (Gamma-Aminobutyric Acid), a chemical that blocks impulses between nerve cells in the brain.

In the current trial, more than 300 participants were randomly assigned either Vitamin B6 or B12 supplements far above the recommended daily intake (approximately 50 times the recommended daily allowance) or a placebo, and took one a day with food for a month.

The study showed that Vitamin B12 had little effect compared to placebo over the trial period, but Vitamin B6 made a statistically reliable difference.

Raised levels of GABA among participants who had taken Vitamin B6 supplements were confirmed by visual tests carried out at the end of the trial, supporting the hypothesis that B6 was responsible for the reduction in anxiety. Subtle but harmless changes in visual performance were detected, consistent with controlled levels of brain activity.

Dr Field said: "Many foods, including tuna, chickpeas and many fruits and vegetables, contain Vitamin B6. However, the high doses used in this trial suggest that supplements would be necessary to have a positive effect on mood.

"It is important to acknowledge that this research is at an early stage and the effect of Vitamin B6 on anxiety in our study was quite small compared to what you would expect from medication. However, nutrition-based interventions produce far fewer unpleasant side effects than drugs, and so in the future people might prefer them as an intervention.

"To make this a realistic choice, further research is needed to identify other nutrition-based interventions that benefit mental wellbeing, allowing different dietary interventions to be combined in future to provide greater results.

"One potential option would be to combine Vitamin B6 supplements with talking therapies such as Cognitive Behavioural Therapy to boost their effect."

 

Journal Reference:

1. David T. Field, Rebekah O. Cracknell, Jessica R. Eastwood, Peter Scarfe, Claire M. Williams, Ying Zheng, Teresa Tavassoli. High‐dose Vitamin B6 supplementation reduces anxiety and strengthens visual surround suppression. Human Psychopharmacology: Clinical and Experimental, 2022; DOI: 10.1002/hup.2852 

Courtesy:

University of Reading. "Vitamin B6 supplements could reduce anxiety and depression." ScienceDaily. ScienceDaily, 19 July 2022. <www.sciencedaily.com/releases/2022/07/220719091209.htm>.

 

 

 

A rhythmic small intestinal microbiome prevents obesity and type 2 diabetes

An estimated 500 to 1,000 bacterial species reside in each person's gut, perhaps numbering 100,000 trillion microorganisms. In a new paper, published July 5, 2022 in Cell Reports, researchers at University of California San Diego School of Medicine used mouse models to explore how diet and feeding patterns affect these intestinal microbes -- and the health of the hosts, particularly with obesity and type 2 diabetes.

In both mice and men, the ileum is the final stretch of the small intestine, connecting to the cecum, the first part of the large intestine. In the ileum, nutrients are drawn out of liquefied food; in the cecum, which also marks the beginning of the colon, the process of extracting water begins.

Both processes are complex, dynamic and profoundly influenced by factors ranging from the types of foods consumed and when, to the microbial residents of the gut, whose presence and behaviors help dictate digestion, absorption of nutrients, vitamin synthesis and development of the immune system.

"It's important to realize that the gut microbiome is constantly changing, not only based on what we're eating, but also based on the time of day," said senior study author Amir Zarrinpar, MD, PhD, assistant professor of medicine at UC San Diego School of Medicine and a gastroenterologist at UC San Diego Health.

"Most researchers are getting snapshots of this constantly shifting environment, which makes it hard to understand what is going on in the gut. With this study, we are trying to get multiple snapshots throughout the day, almost like a movie, to better understand how food and the microbiome interact to affect weight gain and diabetes.

"And what we've learned is that cyclical changes in the gut microbiome are quite important for health since they help with the circadian clock, and with that the regulation and control of glucose, cholesterol and fatty acids -- and overall metabolic health."

In their latest work, Zarrinpar and colleagues further elucidate the impact and interplay of these factors, particularly in terms of the ileum and its unique functions related to digestion and absorption. Specifically, they looked at how diet-induced obesity (DIO) and time-restricted feeding (TRF) alter ileal microbiome composition and transcriptome (the protein-coding part of an organism's genome) in mouse models.

The researchers found that in mouse models, DIO and the absence of TRF (mice could eat as much as they wanted whenever they wanted) resulted in disruptions to gut microbiome rhythms and the signaling pathways that help modulate intestinal clocks. In other words, the mice became fat and unhealthy.

"It is interesting that restricting food access with TRF acts not only through restoration of patterns affected under the unhealthy state, but also through new pathways," said first author Ana Carolina Dantas Machado, PhD, a postdoctoral scholar in Zarrinpar's lab.

"These findings underscore the influence of diet and time restricted feeding patterns in maintaining a healthy gut microbiome, which in turn modulates circadian rhythms that govern metabolic health," said Zarrinpar. "It's a very complicated relationship between the microbiome and the host, with the former helping determine the latter's gastrointestinal functioning and health."

Their work, said the authors, can inform future studies, in particular investigations of how the gut works or how drugs act upon the gut function depending upon the state of the microbiome at a particular time or time of day.

Co-authors include: Steven D. Brown, Amulya Lingaraju, Vignesh Sivaganesh, Cameron Martino, Peng Zhao, Antonio F.M. Pinto, Max W. Chang, R. Alexander Richter Alan R. Saltiel, Rob Knight and Satchidananda Panda, all at UC San Diego; Amandine Chaix, University of Utah; and Alan Saghatelian, Salk Institute for Biological Studies.

Journal Reference:

1. Ana Carolina Dantas Machado, Steven D. Brown, Amulya Lingaraju, Vignesh Sivaganesh, Cameron Martino, Amandine Chaix, Peng Zhao, Antonio F.M. Pinto, Max W. Chang, R. Alexander Richter, Alan Saghatelian, Alan R. Saltiel, Rob Knight, Satchidananda Panda, Amir Zarrinpar. Diet and feeding pattern modulate diurnal dynamics of the ileal microbiome and transcriptome. Cell Reports, 2022; 40 (1): 111008 DOI: 10.1016/j.celrep.2022.111008 

Courtesy:

University of California - San Diego. "A rhythmic small intestinal microbiome prevents obesity and type 2 diabetes." ScienceDaily. ScienceDaily, 5 July 2022. <www.sciencedaily.com/releases/2022/07/220705162154.htm>.

 

Major step forward in fabricating an artificial heart, fit for a human

Heart disease -- the leading cause of death in the U.S. -- is so deadly in part because the heart, unlike other organs, cannot repair itself after injury. That is why tissue engineering, ultimately including the wholesale fabrication of an entire human heart for transplant, is so important for the future of cardiac medicine.

To build a human heart from the ground up, researchers need to replicate the unique structures that make up the heart. This includes recreating helical geometries, which create a twisting motion as the heart beats. It's been long theorized that this twisting motion is critical for pumping blood at high volumes, but proving that has been difficult, in part because creating hearts with different geometries and alignments has been challenging.

Now, bioengineers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed the first biohybrid model of human ventricles with helically aligned beating cardiac cells, and have shown that muscle alignment does, in fact, dramatically increases how much blood the ventricle can pump with each contraction.

This advancement was made possible using a new method of additive textile manufacturing, Focused Rotary Jet Spinning (FRJS), which enabled the high-throughput fabrication of helically aligned fibers with diameters ranging from several micrometers to hundreds of nanometers. Developed at SEAS by Kit Parker's Disease Biophysics Group, FRJS fibers direct cell alignment, allowing for the formation of controlled tissue engineered structures.

The research is published in Science.

"This work is a major step forward for organ biofabrication and brings us closer to our ultimate goal of building a human heart for transplant," said Parker, the Tarr Family Professor of Bioengineering and Applied Physics at SEAS and senior author of the paper.

This work has its roots in a centuries old mystery. In 1669, English physician Richard Lower -- a man who counted John Locke among his colleagues and King Charles II among his patients -- first noted the spiral-like arrangement of heart muscles in his seminal work Tractatus de Corde.

Over the next three centuries, physicians and scientists have built a more comprehensive understanding of the heart's structure but the purpose of those spiraling muscles has remained frustratingly hard to study.

In 1969, Edward Sallin, former chair of the Department of Biomathematics at the University of Alabama Birmingham Medical School, argued that the heart's helical alignment is critical to achieving large ejection fractions -- the percentage of how much blood the ventricle pumps with each contraction.

"Our goal was to build a model where we could test Sallin's hypothesis and study the relative importance of the heart's helical structure," said John Zimmerman, a postdoctoral fellow at SEAS and co-first author of the paper.

To test Sallin's theory, the SEAS researchers used the FRJS system to control the alignment of spun fibers on which they could grow cardiac cells.

The first step of FRJS works like a cotton candy machine -- a liquid polymer solution is loaded into a reservoir and pushed out through a tiny opening by centrifugal force as the device spins. As the solution leaves the reservoir, the solvent evaporates, and the polymers solidify to form fibers. Then, a focused airstream controls the orientation of the fiber as they are deposited on a collector. The team found that by angling and rotating the collector, the fibers in the stream would align and twist around the collector as it spun, mimicking the helical structure of heart muscles.

The alignment of the fibers can be tuned by changing the angle of the collector.

"The human heart actually has multiple layers of helically aligned muscles with different angles of alignment," said Huibin Chang, a postdoctoral fellow at SEAS and co-first author of the paper. "With FRJS, we can recreate those complex structures in a really precise way, forming single and even four chambered ventricle structures."

Unlike 3D printing, which gets slower as features get smaller, FRJS can quickly spin fibers at the single micron scale -- or about fifty times smaller than a single human hair. This is important when it comes to building a heart from scratch. Take collagen for instance, an extracellular matrix protein in the heart, which is also a single micron in diameter. It would take more than 100 years to 3D print every bit of collagen in the human heart at this resolution. FRJS can do it in a single day.

After spinning, the ventricles were seeded with rat cardiomyocyte or human stem cell derived cardiomyocyte cells. Within about a week, several thin layers of beating tissue covered the scaffold, with the cells following the alignment of the fibers beneath.

The beating ventricles mimicked the same twisting or wringing motion present in human hearts.

The researchers compared the ventricle deformation, speed of electrical signaling and ejection fraction between ventricles made from helical aligned fibers and those made from circumferentially aligned fibers. They found on every front, the helically aligned tissue outperformed the circumferentially aligned tissue.

"Since 2003, our group has worked to understand the structure-function relationships of the heart and how disease pathologically compromises these relationships," said Parker. "In this case, we went back to address a never tested observation about the helical structure of the laminar architecture of the heart. Fortunately, Professor Sallin published a theoretical prediction more than a half century ago and we were able to build a new manufacturing platform that enabled us to test his hypothesis and address this centuries-old question."

The team also demonstrated that the process can be scaled up to the size of an actual human heart and even larger, to the size of a Minke whale heart (they didn't seed the larger models with cells as it would take billions of cardiomyocyte cells).

Besides biofabrication, the team also explores other applications for their FRJS platform, such as food packaging.

The Harvard Office of Technology Development has protected the intellectual property relating to this project and is exploring commercialization opportunities.

It was supported in part by the Harvard Materials Research Science and Engineering Center (DMR-1420570, DMR-2011754), the National Institutes of Health with the Center for Nanoscale Systems (S10OD023519) and National Center for Advancing Translational Sciences (UH3TR000522, 1-UG3-HL-141798-01).

Journal Reference:

1. Huibin Chang, Qihan Liu, John F. Zimmerman, Keel Yong Lee, Qianru Jin, Michael M. Peters, Michael Rosnach, Suji Choi, Sean L. Kim, Herdeline Ann M. Ardoña, Luke A. MacQueen, Christophe O. Chantre, Sarah E. Motta, Elizabeth M. Cordoves, Kevin Kit Parker. Recreating the heart’s helical structure-function relationship with focused rotary jet spinning. Science, 2022; 377 (6602): 180 DOI: 10.1126/science.abl6395 

Courtesy:

Harvard John A. Paulson School of Engineering and Applied Sciences. "Major step forward in fabricating an artificial heart, fit for a human: By recreating the helical structure of heart muscles, researchers improve understanding of how the heart beats." ScienceDaily. ScienceDaily, 8 July 2022. <www.sciencedaily.com/releases/2022/07/220708123626.htm>.

 

Shapeshifting microrobots can brush and floss teeth

 A shapeshifting robotic microswarm may one day act as a toothbrush, rinse, and dental floss in one. The technology, developed by a multidisciplinary team at the University of Pennsylvania, is poised to offer a new and automated way to perform the mundane but critical daily tasks of brushing and flossing. It's a system that could be particularly valuable for those who lack the manual dexterity to clean their teeth effectively themselves.

The building blocks of these microrobots are iron oxide nanoparticles that have both catalytic and magnetic activity. Using a magnetic field, researchers could direct their motion and configuration to form either bristle-like structures that sweep away dental plaque from the broad surfaces of teeth, or elongated strings that can slip between teeth like a length of floss. In both instances, a catalytic reaction drives the nanoparticles to produce antimicrobials that kill harmful oral bacteria on site.

Experiments using this system on mock and real human teeth showed that the robotic assemblies can conform to a variety of shapes to nearly eliminate the sticky biofilms that lead to cavities and gum disease. The Penn team shared their findings establishing a proof-of-concept for the robotic system in the journal ACS Nano.

"Routine oral care is cumbersome and can pose challenges for many people, especially those who have hard time cleaning their teeth" says Hyun (Michel) Koo, a professor in the Department of Orthodontics and divisions of Community Oral Health and Pediatric Dentistry in Penn's School of Dental Medicine and co-corresponding author on the study. "You have to brush your teeth, then floss your teeth, then rinse your mouth; it's a manual, multi-step process. The big innovation here is that the robotics system can do all three in a single, hands-free, automated way."

"Nanoparticles can be shaped and controlled with magnetic fields in surprising ways," says Edward Steager, a senior research investigator in Penn's School of Engineering and Applied Science and co-corresponding author. "We form bristles that can extend, sweep, and even transfer back and forth across a space, much like flossing. The way it works is similar to how a robotic arm might reach out and clean a surface. The system can be programmed to do the nanoparticle assembly and motion control automatically."

Disrupting oral care technology

"The design of the toothbrush has remained relatively unchanged for millennia," says Koo.

While adding electric motors elevated the basic 'bristle-on-a-stick format', the fundamental concept has remained the same. "It's a technology that has not been disrupted in decades."

Several years ago, Penn researchers within the Center for Innovation & Precision Dentistry (CiPD), of which Koo is a co-director, took steps toward a major disruption, using this microrobotics system.

Their innovation arose from a bit of serendipity. Research groups in both Penn Dental Medicine and Penn Engineering were interested in iron oxide nanoparticles but for very different reasons. Koo's group was intrigued by the catalytic activity of the nanoparticles. They can activate hydrogen peroxide to release free radicals that can kill tooth-decay-causing bacteria and degrade dental plaque biofilms. Meanwhile Steager and engineering colleagues, including Dean Vijay Kumar and Professor Kathleen Stebe, co-director of CiPD, were exploring these nanoparticles as building blocks of magnetically controlled microrobots.

With support from Penn Health Tech and the National Institutes of Health's National Institute of Dental and Craniofacial Research, the Penn collaborators married the two applications in the current work, constructing a platform to electromagnetically control the microrobots, enabling them to adopt different configurations and release antimicrobials on site to effectively treat and clean teeth.

"It doesn't matter if you have straight teeth or misaligned teeth, it will adapt to different surfaces," says Koo. "The system can adjust to all the nooks and crannies in the oral cavity."

The researchers optimized the motions of the microrobots on a small slab of tooth-like material. Next, they tested the microrobots' performance adjusting to the complex topography of the tooth surface, interdental surfaces, and the gumline, using 3D-printed tooth models based on scans of human teeth from the dental clinic. Finally, they trialed the microrobots on real human teeth that were mounted in such a way as to mimic the position of teeth in the oral cavity.

On these various surfaces, the researchers found that the microrobotics system could effectively eliminate biofilms, clearing them of all detectable pathogens. The iron oxide nanoparticles have been FDA approved for other uses, and tests of the bristle formations on an animal model showed that they did not harm the gum tissue.

Indeed, the system is fully programmable; the team's roboticists and engineers used variations in the magnetic field to precisely tune the motions of the microrobots as well as control bristle stiffness and length. The researchers found that the tips of the bristles could be made firm enough to remove biofilms but soft enough to avoid damage to the gums.

The customizable nature of the system, the researchers say, could make it gentle enough for clinical use, but also personalized, able to adapt to the unique topographies of a patient's oral cavity.

To advance this technology to the clinic, the Penn team is continuing to optimize the robots' motions and considering different means of delivering the microrobots through mouth-fitting devices.

They're eager to see their device help patients.

"We have this technology that's as or more effective as brushing and flossing your teeth but doesn't require manual dexterity," says Koo. "We'd love to see this helping the geriatric population and people with disabilities. We believe it will disrupt current modalities and majorly advance oral health care."

Hyun (Michel) Koo is a professor in the Department of Orthodontics and divisions of Community Oral Health and Pediatric Dentistry in the School of Dental Medicine and co-director of the Center for Innovation & Precision Dentistry at the University of Pennsylvania.

Edward Steager is a senior research investigator in Penn's School of Engineering and Applied Science.

Koo and Steager's coauthors on the paper are Penn Dental Medicine's Min Jun Oh, Alaa Babeer, Yuan Liu, and Zhi Ren and Penn Engineering's Jingyu Wu, David A. Issadore, Kathleen J. Stebe, and Daeyeon Lee.

This work was supported in part by the National Institute for Dental and Craniofacial Research (grants DE025848 and DE029985), Procter & Gamble, and the Postdoctoral Research Program of Sungkyunkwan University.

Journal Reference:

1. Min Jun Oh, Alaa Babeer, Yuan Liu, Zhi Ren, Jingyu Wu, David A. Issadore, Kathleen J. Stebe, Daeyeon Lee, Edward Steager, Hyun Koo. Surface Topography-Adaptive Robotic Superstructures for Biofilm Removal and Pathogen Detection on Human Teeth. ACS Nano, 2022; DOI: 10.1021/acsnano.2c01950 

Courtesy:

University of Pennsylvania. "Shapeshifting microrobots can brush and floss teeth: Hands-free system could effectively automate the treatment and removal of tooth-decay-causing bacteria and dental plaque, research shows." ScienceDaily. ScienceDaily, 5 July 2022. <www.sciencedaily.com/releases/2022/07/220705194142.htm>.

 

The importance of elders

According to long-standing canon in evolutionary biology, natural selection is cruelly selfish, favoring traits that help promote reproductive success. This usually means that the so-called "force" of selection is well equipped to remove harmful mutations that appear during early life and throughout the reproductive years. However, by the age fertility ceases, the story goes that selection becomes blind to what happens to our bodies. After the age of menopause, our cells are more vulnerable to harmful mutations. In the vast majority of animals, this usually means that death follows shortly after fertility ends.

Which puts humans (and some species of whale) in a unique club: animals that continue to live long after their reproductive lives end. How is it that we can live decades in selection's shadow?

"From the perspective of natural selection, long post-menopausal life is a puzzle," said UC Santa Barbara anthropology professor Michael Gurven. In most animals, including chimpanzees -- our closest primate brethren -- this link between fertility and longevity is very pronounced, where survival drops in sync with the ability to reproduce. Meanwhile in humans, women can live for decades after their ability to have children ends. "We don't just gain a few extra years -- we have a true post-reproductive life stage," Gurven said.

In a paper published in the Proceedings of the National Academy of Sciences, senior author Gurven, with former UCSB postdoctoral fellow and population ecologist Raziel Davison, challenge the longstanding view that the force of natural selection in humans must decline to zero once reproduction is complete.

They assert that a long post-reproductive lifespan is not just due to recent advancements in health and medicine. "The potential for long life is part of who we are as humans, an evolved feature of the life course," Gurven said.

The secret to our success? Our grandparents.

"Ideas about the potential value of older adults have been floating around for awhile," Gurven said. "Our paper formalizes those ideas, and asks what the force of selection might be once you take into account the contributions of older adults."

For example, one of the leading ideas for human longevity is called the Grandmother Hypothesis -- the idea that, through their efforts, maternal grandmothers can increase their fitness by helping improve the survival of their grandchildren, thereby enabling their daughters to have more children. Such fitness effects help ensure that the grandmother's DNA is passed down.

"And so that's not reproduction, but it's sort of an indirect reproduction. The ability to pool resources, and not just rely on your own efforts, is a game changer for highly social animals like humans," Davison said.

In their paper, the researchers take the kernel of that idea -- intergenerational transfers, or resource sharing between old and young -- and show that it, too, has played a fundamental role in the force of selection at different ages. Food sharing in non-industrial societies is perhaps the most obvious example.

"It takes up to two decades from birth before people produce more food than they're consuming," said Gurven, who has studied the economy and demography of the Tsimané and other indigenous groups of South America. A lot of food has to be procured and shared to get kids to the point where they can fend for themselves and be productive group members. Adults fill most of this need with their ability to obtain more food than they need for themselves, a provisioning strategy that has sustained pre-industrial societies for ages and also carries over into industrialized societies.

"In our model, the large surplus that adults produce helps improve the survival and fertility of close kin, and of other group members who reliably share their food, too," Davison said. "Viewed through the lens of food production and its effects, it turns out that the indirect fitness value of adults is also highest among reproductive-aged adults. But using demographic and economic data from multiple hunter-gatherers and horticulturalists, we find that the surplus provided by older adults also generates positive selection for their survival. We calculate all this extra fitness in late adulthood to be worth up to a few extra kids!"

"We show that elders are valuable, but only up to a point," contends Gurven. "Not all grandmothers are worth their weight. By about their mid-seventies, hunter-gatherers and farmers end up soaking up more resources than they provide. Plus, by their mid-seventies, most of their grandkids won't be dependents anymore, and so the circle of close kin who stand to benefit from their help is small."

But food isn't everything. Beyond getting fed, children are also taught and socialized, trained in relevant skills and worldviews. This is where older adults can make their biggest contributions: While they don't contribute as much to the food surplus, they have the accumulation of a lifetime of skills they can deploy to ease the burden of childcare on parents, as well as knowledge and training that they can pass on to their grandchildren.

"Once you take into account that elders are also actively involved in helping others forage, then it adds even more fitness value to their activity and to them being alive," Gurven said. "Not only do elders contribute to the group, but their usefulness helps ensure that they also receive from the surpluses, protections and care from their group. In other words, interdependence runs both ways, from old to young, and young to old."

"If you're part of my social world, there might be some kickback," Davison explained. "So to the extent that we're interdependent, I'm vested in your interest, beyond just simple kinship. I'm interested in getting you to be as skilled as possible because some of your productivity could help me down the road."

Gurven and Davison found that rather than our long lifespans opening up opportunities that led to a human-like foraging economy and social behavior, the reverse is more likely -- our skills-intensive strategies and long-term investments in the health of the group preceded and evolved with our shift to our particular human life history, with its extended childhood and unusually long post-reproductive stage.

In contrast, chimpanzees -- who represent our best guess as to what humans' last common ancestor may have been like -- are able to forage for themselves by age 5. However, their foraging activities require less skill, and they produce minimal surplus. Even so, the authors show that if a chimpanzee-like ancestor would share their food more widely, they could still generate enough indirect fitness contributions to increase the force of selection in later adulthood.

"What this suggests is that human longevity is really a story about cooperation," said Gurven. "Chimpanzee grandmothers are rarely observed doing anything for their grandkids."

Though the authors say their work is more about how the capacity for long life came to first exist in the Homo lineage, the implication that we owe it to elders everywhere is an important reminder looking forward.

"Despite elders being far more numerous today than ever before in the past, there's still much ageism and underappreciation of older adults," Gurven said. "When COVID seemed to be most deadly just for older adults, many shrugged their shoulders about the urgency of lockdown or other major precautions.

"Much of the huge value of our elders goes untapped," he added. "It's time to think seriously about how to reconnect the generations, and harness some of that elder wisdom and expertise."

Journal Reference:

1. Raziel Davison, Michael Gurven. The importance of elders: Extending Hamilton’s force of selection to include intergenerational transfers. Proceedings of the National Academy of Sciences, 2022; 119 (28) DOI: 10.1073/pnas.2200073119 

Courtesy:

University of California - Santa Barbara. "The importance of elders: Researchers argue that the long human lifespan is due in part to the contributions of older adults." ScienceDaily. ScienceDaily, 7 July 2022. <www.sciencedaily.com/releases/2022/07/220707141755.htm>.