Learning Digital Photography Improves Cognitive Function in Older Adults

In my latest 3Quarksdaily column, I discuss the issue of ageism (prejudice against the elderly) and a very well designed new study which compares different forms of cognitive training in older adults. There is a lot of misinformation floating about on how vitamin supplements or solving word puzzles may improve cognitive function, but there is little scientific data available to back it up. The biggest strength of this study is that it used appropriate controls: The enrolled adults were either enrolled in 14 weeks of classes in which they acquired new skills or spent similar amounts of time in social activities or watched educational documentaries and solved puzzles on their own.

 

The recent study “The Impact of Sustained Engagement on Cognitive Function in Older Adults: The Synapse Project” published in the journal Psychological Science by the psychology researcher Denise Park and her colleagues at the University of Texas at Dallas is an example of an extremely well-designed study which attempts to tease out the benefits of participating in a structured activity versus receiving formal education and acquiring new skills. The researchers assigned subjects with a mean age of 72 years (259 participants were enrolled, but only 221 subjects completed the whole study) to participate in 14-week program in one of five intervention groups: 1) learning digital photography, 2) learning how to make quilts, 3) learning both digital photography and quilting (half of the time spent in each program), 4) a “social condition” in which the members participated in a social club involving activities such as cooking, playing games, watching movies, reminiscing, going on regular field trips but without the acquisition of any specific new skills or 5) a “placebo condition” in which participants were provided with documentaries, informative magazines, word games and puzzles, classical-music CDs and asked to perform and log at least 15 hours a week of such activities. None of the participants carried a diagnosis of dementia and they were novices to the areas of digital photography or quilting. Upon subsequent review of the activities in each of the five intervention groups, it turned out that each group spent an average of about 16-18 hours per week in the aforementioned activities, without any significant difference between the groups. Lastly, a sixth group of participants was not enrolled in any specific program but merely asked to keep a log of their activities and used as a no-intervention control.

When the researchers assessed the cognitive skills of the participants after the 14-week period, the type of activity they had been enrolled in had a significant impact on their cognition. For example, the participants in the photography class had a much greater degree of improvement in their episodic memory and their visuospatial processing than the placebo condition. On the other hand, cognitive processing speed of the participants increased most in the dual condition group (photography and quilting) as well as the social condition. The general trend was that the groups which placed the highest cognitive demands on the participants and also challenged them to be creative (acquiring digital photography skills, learning to make quilts) showed the greatest improvements.

However, there are key limitations of the study. Since only 221 participants were divided across six groups, each individual group was fairly small. Repeating this study with a larger sample would increase the statistical power of the study and provide more definitive results. Furthermore, the cognitive assessments were performed soon after completion of the 14-week programs. Would the photography group show sustained memory benefits even a year after completion of the 14-week program? Would the participants continue to be engaged in digital photography long after completion of the respective courses?

Despite these limitations, there is an important take-home message of this study: Cognitive skills in older adults can indeed be improved, especially if they are exposed to an unfamiliar terrain and asked to actively acquire new cognitive skills. Merely watching educational documentaries or completing puzzles (“placebo condition”) is not enough. This research will likely spark many future studies which will help define the specific mechanisms of how acquiring new skills leads to improved memory function and also studies that perhaps individualize cognitive training. Some older adults may benefit most from learning digital photography, others might benefit from acquiring science skills or participating in creative writing workshops. This research also gives us hope as to how we can break the vicious cycle of ageism in which older citizens are marginalized because of cognitive decline, but this marginalization itself further accelerates their decline. By providing opportunities to channel their creativity, we can improve their cognitive function and ensure that they remain engaged in the community.

 

If you are also interested in how this study fits into the broader context of ageism, please read the complete article at 3QD.

 

Denise C. Park, Jennifer Lodi-Smith, Linda Drew, Sara Haber, Andrew Hebrank, Gérard N. Bischof, & Whitley Aamodt (2013). The Impact of Sustained Engagement on Cognitive Function in Older Adults: The Synapse Project Psychological Science DOI: 10.1177/0956797613499592

“Inflamm-Aging”: Inflammatory Signals in the Brain Regulate the Lifespan of Mice

The hypothalamus is located at the base of the brain and in adult humans, it has a volume of only 4cm³, less than half a percent of the total adult human brain volume. Despite its small size, the hypothalamus is one of the most important control centers in our brain because it functions as the major interface between two regulatory systems in our body: The nervous system and the endocrine (hormonal) system. It consists of many subunits (nuclei) which continuously sense inputs and then respond to these inputs by releasing neurotransmitters or hormones that regulate a broad range of vital functions, such as our metabolism, appetite, thirst, reproduction, temperature and even our internal timing system, the circadian clock. As if this huge workload wasn’t enough, researchers have now uncovered an additional role for the hypothalamus: regulating lifespan.

The recent paper “Hypothalamic programming of systemic ageing involving IKK-β,NF-κB and GnRH” published in the journal Nature (published online May 1, 2013) by Guo Zhang and colleagues at the Albert Einstein College of Medicine in New York used elegant genetic mouse models to either continuously activate or continuously suppress the function of the NF-κB protein in the hypothalamus. This protein is a key transcription factor which is found in most organs and tissues and turns on genes in response to an inflammatory stimulus. The researchers were thus able to artificially create an internal scenario in which the hypothalamus was receiving a continuous “inflammation on” or “inflammation off” input without having to provide any external infectious or inflammatory agents. The results were quite striking. Continuous activation of the inflammatory NF-κB pathway in the hypothalamus resulted in a reduction of overall lifespan in the mice, but it also resulted in a loss of muscle mass, bone mass, and cognitive function – the mice showed signs of accelerated aging. An even more remarkable finding was that continuous suppression of the inflammatory pathway extended the lifespan of the mice when compared to their littermates that did not undergo any genetic modifications. Not only did these mice live longer (median lifespan increased by 23%), but they also exhibited significantly less physical and cognitive decline than regular mice!

To investigate the mechanism by which the suppression of inflammatory signals could result in such a profound increase in longevity and functional capacity, the researchers studied Gonadotropin Releasing Hormone (GnRH), one of the major hormones released by the hypothalamus which in turn regulates the release of reproductive hormones. They found that aging or inflammatory activation indeed suppressed GnRH release, whereas inhibition of the inflammatory signaling was able to restore GnRH levels. More importantly, simply injecting the mice with GnRH was able to prevent the physical and cognitive decline in the aging mice. How the injections of GnRH were able to restore muscle mass and even cognitive function was not evaluated in the study, but the researchers did observe that the brain showed increased evidence of neuron growth, which could explain the anti-aging effects of GnRH.

This paper is not the first to link inflammation to aging, but it is the first to show that localized inflammation signals in the hypothalamus can have such a profound effect on the lifespan of mice and it is also the first to propose that suppression of GnRH may be the reason for this inflammation-aging link. As with all important scientific papers, this study raises more questions than it answers. Is GnRH not just a regulator of sex hormones, but does it also exert effects on neurons and muscle cells that are independent of its role as a regulator of reproductive hormones? The mice with prolonged life-spans were all studied in a laboratory setting and thus not exposed to infectious agents that mice (or humans, for that matter) living in the wild commonly encounter. Would suppression of the NF-κB pathway in the hypothalamus possibly compromise their ability to fend off infections or other natural forms of inflammation? It is also not clear whether the GnRH link would apply to all mammals such humans, since aging female primates have higher, (not lower!) GnRH levels. These are all questions that lie beyond the scope of this paper and they need to be addressed in future papers.

However, there are some major limitations of this study and the proposed new hypothalamus-inflammation-GnRH-aging model. First, there is one rather obvious experiment that is missing. The researchers showed that manipulating NF-κB in the hypothalamus can have a major effect on the lifespan and the cognitive as well as physical function, but for some reason the researchers did not show the results from a rather simple experiment: Does GnRH alone extend the lifespan? If GnRH were really the main pathway by which the hypothalamus regulates aging, than giving GnRH ought to have extended the lifespan of the mice.

A second limitation of the paper is that it does not distinguish between general functional decline versus decreased regeneration. Biological aging is characterized by a gradual functional decline over time, but this is due to a combination of at least two parallel processes. Existing cells and tissues accumulate damaged and become dysfunctional and regenerative stem cells or progenitor cells become exhausted and cannot keep up with the repair. This study does not assess whether increased NF-κB activation in the hypothalamus causes more cellular dysfunction, whether it merely inhibits the regenerative repair process or whether it affects both. The researchers did not perform assessments of cellular aging, such as measuring the expression levels of the cellular aging regulator p16 or quantify oxidative stress. Therefore, it is unclear whether NF-κB activation in the hypothalamus had any impact on the cellular aging (senescence) program in the brain, muscles or elsewhere in the body.

Another key limitation is that the hypothalamus has so many functions other than GnRH release, which could all contribute to aging and changes in the lifespan of the mice. The authors themselves have previously published that NF-κB in the hypothalamus regulates the link between obesity and high blood pressure and multiple other groups have already shown that the hypothalamus may affect aging via its role in metabolic regulation. Unfortunately, the current study glosses over the potential role of metabolism and high blood pressure, which could explain the observed longevity effects and instead just focuses on the more provocative but less substantiated idea of GnRH as the aging regulator.

Due to these limitations, we still have to await additional studies that confirm the role of GnRH as the target for NF-κB activation in the hypothalamus and this link between inflammation, aging and the hypothalamus.

We should also remember that biological aging is just one aspect of aging. As André Maurois once wrote, “Old age is far more than white hair, wrinkles, the feeling that it is too late and the game finished, that the stage belongs to the rising generations. The true evil is not the weakening of the body, but the indifference of the soul.”

 

Image credit: A GIF depicting the Hypothalamus “BodyParts3D”, © The Database Center for Life Science – Creative Commons license via Wikimedia Commons, Painting by John Haberle (1856-1933) – Time and Eternity, via Wikimedia Commons

 

Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, & Cai D (2013). Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature, 497 (7448), 211-216 PMID: 23636330

Immune Cells Can Remember Past Lives

The generation of induced pluripotent stem cells (iPSCs) is one of the most fascinating discoveries in the history of stem cell biology. John Gurdon and Shinya Yamanaka received the 2012 Nobel Prize for showing that adult cells could be induced to become embryonic-like stem cells (iPSCs). Many stem cell laboratories now routinely convert skin cells or blood cells from an adult patient into iPSCs. The stem cell properties of the generated iPSCs then allow researchers to convert them into a desired cell type, such as heart cells (cardiomyocytes) or brain cells (neurons), which can then be used for cell-based therapies or for the screening of novel drugs. The initial conversion of adult cells to iPSCs is referred to as “reprogramming” and is thought to represent a form of rejuvenation, because the adult cell appears to lose its adult cell identity and reverts to an immature embryonic-like state. However, we know surprisingly little about the specific mechanisms that allow adult cells to become embryonic-like. For example, how does a blood immune cell such as a lymphocyte lose its lymphocyte characteristics during the reprogramming process? Does the lymphocyte that is converted into an immature iPSC state “remember” that it used to be a lymphocyte? If yes, does this memory affect what types of cells the newly generated iPSCs can be converted into, i.e. are iPSCs derived from lymphocytes very different from iPSCs that are derived from skin cells?

There have been a number of recent studies that have tried to address the question of the “memory” in iPSCs, but two recent papers published in the January 3, 2013 issue of the journal Cell Stem Cell provide some of the most compelling proofs of an iPSC “memory” and also show that this “memory” could be used for therapeutic purposes. In the paper “Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8+ T Cells“, Vizcardo and colleagues studied the reprogramming of T-lymphocytes derived from the tumor of a melanoma patient. Mature T-lymphocytes are immune cells that can recognize specific targets, depending on what antigen they have been exposed to. The tumor infiltrating cells used by Vizcardo and colleagues have been previously shown to recognize the melanoma tumor antigen MART-1. The researchers were able to successfully generate iPSCs from the T-lymphocytes, and they then converted the iPSCs back to T-lymphocytes. What they found was that the newly generated T-lymphocytes expressed a receptor that was specific for the MART tumor antigen. Even though the newly generated T-lymphocytes had not been exposed to the tumor, they had retained their capacity to respond to the melanoma antigen. The most likely explanation for this is that the generated iPSCs “remembered” their previous exposure to the tumor in their past lives as T-lymphocytes before they had been converted to embryonic-like iPSCs and then “reborn” as new T-lymphocytes. The iPSC reprogramming apparently did not wipe out their “memory”.

This finding has important therapeutic implications. One key problem that the immune system faces when fighting a malignant tumor is that the demand for immune cells outpaces their availability. The new study suggests that one can take activated immune cells from a cancer patient, convert them to the iPSC state, differentiate them back into rejuvenated immune cells, expand them and inject them back into the patient. The expanded and rejuvenated immune cells would retain their prior anti-tumor memory, be primed to fight the tumor and thus significantly augment the ability of the immune system to slow down the tumor growth.

The paper by Vizcardo and colleagues did not actually show the rejuvenation and anti-tumor efficacy of the iPSC-derived T-lymphocytes and this needs to be addressed in future studies. However, the paper “Generation of Rejuvenated Antigen-Specific T Cells by Reprogramming to Pluripotency and Redifferentiation” by Nishimura and colleagues in the same issue of Cell Stem Cell, did address the rejuvenation question, albeit in a slightly different context. This group of researchers obtained T-lymphocytes from a patient with HIV, then generated iPSC and re-differentiated the iPSCs back into T-lymphocytes. Similar to what Vizcardo and colleagues had observed, Nishimura and colleagues found that their iPSC derived T-lymphocytes retained an immunological memory against HIV antigens. Importantly, the newly derived T-lymphocytes were highly proliferative and had longer telomeres. The telomeres are chunks of DNA that become shorter as cells age, so the lengthening of telomeres and the high growth rate of the iPSC derived T-lymphocytes were both indicators that the iPSC reprogramming process had made the cells younger while also retaining their “memory” or ability to respond to HIV.

Further studies are now needed to test whether adding the rejuvenated cells back into the body does actually help prevent tumor growth and can treat HIV infections. There is also a need to ensure that the cells are safe and the rejuvenation process itself did not cause any harmful genetic changes. Long telomeres have been associated with the formation of tumors and one has to make sure that the iPSC-derived lymphocytes do not become malignant. These two studies represent an exciting new development in iPSC research. They not only clearly document that iPSCs retain a memory of the original adult cell type they are derived from but they also show that this memory can be put to good use. This is especially true for immune cells, because retaining an immunological memory allows rejuvenated iPSC-derived immune cells to resume the fight against a tumor or a virus.

 

Image credit: “Surface of HIV infected macrophage” by Sriram Subramaniam at the National Cancer Institute (NCI) via National Institutes of Health Image Bank