Top Brain, Bottom Brain - a user's manual from Kosslyn and Miller

I thought I would point to a recent book authored by Kosslyn and Miller:  “Top Brain - Bottom Brain: Surprising Insights into How You Think.” They make a good effort to communicate (co-author Miller is a professional journalist/author), yet it is a tough slog at points.

Their basic simplification is to describe the top and the bottom parts of the brain as performing different sorts of tasks. The bottom-brain system classifies and interprets sensory information from the world, and the top-brain system formulates and executes plans. Here is the standard brain graphic from their introduction:

You can have four separate ways of arranging a set of opposites like top and bottom, and they make these into four personality types distinguished by different relative activities of the two.:

To do a disservice to their more balanced and extended presentation, I cut to the chase with an irreverent condensation:

The movers appear to be your winners, top brain action people who actually also use the bottom half to pay attention to the consequences of their actions and use the feedback.

The stimulator is more the ‘damn the cannons, full speed ahead’ kind of person, less inclined to attend to the consequences of their actions and know when enough is enough.

The Perceivers are mainly bottom brain perceivers and interpreters, but unlikely to initiate top brain detailed or complex plans.

Finally, the people with lazy top and bottom brains are ‘whatever…’ types, absorbed by local events and immediate imperatives, passively responsive to ongoing situations, i.e. the U.S. electorate.

Chapter 13 presents a test for the reader to determine his or her own individual style. They suggest that although you may not always rely on the same mode in every context, peoples' responses to the test indicate that they do operate in a single mode most of the time. You can take the test in the book, or take it online at www.TopBrainBottomBrain.com and have your score computed automatically.

Judging a man by the width of his face.

Valentine et al. make interesting observations in a speed-dating context. The effect of higher facial width-to-height ratio on short-term but not long-term relationships is compatible with the idea that more dominant men who are selected for mating because of their good health and prowess may also more likely to be less faithful and less investing as fathers:

Previous research has shown that men with higher facial width-to-height ratios (fWHRs) have higher testosterone and are more aggressive, more powerful, and more financially successful. We tested whether they are also more attractive to women in the ecologically valid mating context of speed dating. Men’s fWHR was positively associated with their perceived dominance, likelihood of being chosen for a second date, and attractiveness to women for short-term, but not long-term, relationships. Perceived dominance (by itself and through physical attractiveness) mediated the relationship between fWHR and attractiveness to women for short-term relationships. Furthermore, men’s perceptions of their own dominance showed patterns of association with mating desirability similar to those of fWHR. These results support the idea that fWHR is a physical marker of dominance. This is the first study to show that male dominance and higher fWHRs are attractive to women for short-term relationships in a controlled and interactive situation that could actually lead to mating and dating.

Over the hill at 24

Great....the continuous stream of papers documenting cognitive aging in adults and seniors, many noted in MindBlog, has how lowered the bar even further. Thompson et al. find a slowing of response times in a video game beginning at 24 years of age.

Typically studies of the effects of aging on cognitive-motor performance emphasize changes in elderly populations. Although some research is directly concerned with when age-related decline actually begins, studies are often based on relatively simple reaction time tasks, making it impossible to gauge the impact of experience in compensating for this decline in a real world task. The present study investigates age-related changes in cognitive motor performance through adolescence and adulthood in a complex real world task, the real-time strategy video game StarCraft 2. In this paper we analyze the influence of age on performance using a dataset of 3,305 players, aged 16-44, collected by Thompson, Blair, Chen & Henrey. Using a piecewise regression analysis, we find that age-related slowing of within-game, self-initiated response times begins at 24 years of age. We find no evidence for the common belief expertise should attenuate domain-specific cognitive decline. Domain-specific response time declines appear to persist regardless of skill level. A second analysis of dual-task performance finds no evidence of a corresponding age-related decline. Finally, an exploratory analyses of other age-related differences suggests that older participants may have been compensating for a loss in response speed through the use of game mechanics that reduce cognitive load.

Training emotions - a brief video from The Brain Club

I received an email recently from "The Brain Club" pointing me to the series of brief video presentations they are developing over time. I thought the presentation by Amit Etkin at Stanford Univ. was very effective. I'm including that video in this post. It describes the results of a meta-analysis of many papers that shows that in anxious and depressed individuals the brain's amygdala, insula, and cingulate are over-reactive while the prefrontal cortex is under-reactive. (i.e. the downstairs is over-riding the upstairs of our brains.) Cognitive training exercises available on the web that reinforce a positivity bias and enhance working memory lessen this upstairs/downstairs imbalance, and a brief review by Subramaniam and Vinogradov shows MRI data indicating that it is accompanied by enhancement of medial prefrontal activity.

 

Here is a slightly larger version of the figure from the meta-analysis paper showing the downstair (yellow) and upstairs (blue) regions whose activity changes with training.

A more through summary of cognitive training for impaired neural systems can be found in Vinogradov et al.

Attributing awareness to oneself and others.

Kelley et al. make some fascinating observations. I pass on their statement of the significance of the work and their abstract:

Significance

What is the relationship between your own private awareness of events and the awareness that you intuitively attribute to the people around you? In this study, a region of the human cerebral cortex was active when people attributed sensory awareness to someone else. Furthermore, when that region of cortex was temporarily disrupted, the person’s own sensory awareness was disrupted. The findings suggest a fundamental connection between private awareness and social cognition.

Abstract

This study tested the possible relationship between reported visual awareness (“I see a visual stimulus in front of me”) and the social attribution of awareness to someone else (“That person is aware of an object next to him”). Subjects were tested in two steps. First, in an fMRI experiment, subjects were asked to attribute states of awareness to a cartoon face. Activity associated with this task was found bilaterally within the temporoparietal junction (TPJ) among other areas. Second, the TPJ was transiently disrupted using single-pulse transcranial magnetic stimulation (TMS). When the TMS was targeted to the same cortical sites that had become active during the social attribution task, the subjects showed symptoms of visual neglect in that their detection of visual stimuli was significantly affected. In control trials, when TMS was targeted to nearby cortical sites that had not become active during the social attribution task, no significant effect on visual detection was found. These results suggest that there may be at least some partial overlap in brain mechanisms that participate in the social attribution of sensory awareness to other people and in attributing sensory awareness to oneself.

Poor people judge more harshly.

From Pitesa and Thau:

In the research presented here, we tested the idea that a lack of material resources (e.g., low income) causes people to make harsher moral judgments because a lack of material resources is associated with a lower ability to cope with the effects of others’ harmful behavior. Consistent with this idea, results from a large cross-cultural survey (Study 1) showed that both a chronic (due to low income) and a situational (due to inflation) lack of material resources were associated with harsher moral judgments. The effect of inflation was stronger for low-income individuals, whom inflation renders relatively more vulnerable. In a follow-up experiment (Study 2), we manipulated whether participants perceived themselves as lacking material resources by employing different anchors on the scale they used to report their income. The manipulation led participants in the material-resources-lacking condition to make harsher judgments of harmful, but not of nonharmful, transgressions, and this effect was explained by a sense of vulnerability. Alternative explanations were excluded. These results demonstrate a functional and contextually situated nature of moral psychology.

Memory reactivation in aging versus young brains.

Given my status as a senior aging person I always note the passing article that chronicles yet another way in which the equipment upstairs is losing it. Here is a bit from St-Laurent et al. that shows that the greater difficulty senior people have in recalling past experiences, replaying them, is not in the quality of their initial perceptions, but in fetching them up during recall attempts. (I've thought about preparing a longer written piece or talk on brain changes in aging, drawn mainly from MindBlog posts, but have decided I would rather go for more cheerful topics.)

We investigated how aging affects the neural specificity of mental replay, the act of conjuring up past experiences in one's mind. We used functional magnetic resonance imaging (fMRI) and multivariate pattern analysis to quantify the similarity between brain activity elicited by the perception and memory of complex multimodal stimuli. Young and older human adults viewed and mentally replayed short videos from long-term memory while undergoing fMRI. We identified a wide array of cortical regions involved in visual, auditory, and spatial processing that supported stimulus-specific representation at perception as well as during mental replay. Evidence of age-related dedifferentiation was subtle at perception but more salient during mental replay, and age differences at perception could not account for older adults' reduced neural reactivation specificity. Performance on a post-scan recognition task for video details correlated with neural reactivation in young but not in older adults, indicating that in-scan reactivation benefited post-scan recognition in young adults, but that some older adults may have benefited from alternative rehearsal strategies. Although young adults recalled more details about the video stimuli than older adults on a post-scan recall task, patterns of neural reactivation correlated with post-scan recall in both age groups. These results demonstrate that the mechanisms supporting recall and recollection are linked to accurate neural reactivation in both young and older adults, but that age affects how efficiently these mechanisms can support memory's representational specificity in a way that cannot simply be accounted for by degraded sensory processes.

Enhancing or lowering performance monitoring activity of our brains.

Wow, here is a fascinating observation. Small electrical currents applied to our medial frontal cortex can either enhance or abolish our brains' error detection and feedback adjustment activities:

Adaptive human behavior depends on the capacity to adjust cognitive processing after an error. Here we show that transcranial direct current stimulation of medial–frontal cortex provides causal control over the electrophysiological responses of the human brain to errors and feedback. Using one direction of current flow, we eliminated performance-monitoring activity, reduced behavioral adjustments after an error, and slowed learning. By reversing the current flow in the same subjects, we enhanced performance-monitoring activity, increased behavioral adjustments after an error, and sped learning. These beneficial effects fundamentally improved cognition for nearly 5 h after 20 min of noninvasive stimulation. The stimulation selectively influenced the potentials indexing error and feedback processing without changing potentials indexing mechanisms of perceptual or response processing. Our findings demonstrate that the functioning of mechanisms of cognitive control and learning can be up- or down-regulated using noninvasive stimulation of medial–frontal cortex in the human brain.

Caloric restriction and longevity.

I thought I would pass on this recent open access Nature article by the Univ. of Wisconsin group studying the effects of caloric restriction in Rhesus monkeys, studies meant to be more relevant to us humans that the mouse work showing increased health and longevity caused by dietary restriction. They suggest that a reason that an NIH study found less striking effects was that the controls in the NIH study were also effectively calorically restricted.

Caloric restriction (CR) without malnutrition increases longevity and delays the onset of age-associated disorders in short-lived species, from unicellular organisms to laboratory mice and rats. The value of CR as a tool to understand human ageing relies on translatability of CR’s effects in primates. Here we show that CR significantly improves age-related and all-cause survival in monkeys on a long-term ~30% restricted diet since young adulthood. These data contrast with observations in the 2012 NIA intramural study report, where a difference in survival was not detected between control-fed and CR monkeys. A comparison of body weight of control animals from both studies with each other, and against data collected in a multi-centred relational database of primate ageing, suggests that the NIA control monkeys were effectively undergoing CR. Our data indicate that the benefits of CR on ageing are conserved in primates.

Is consciousness in control? Does it matter?

I want to pass on a clip from SelfAwarePatterns that is as succinct a summary as I have seen (better than the one in my "I-Illusion" lecture) of the largely futile free will debate (the subject of many mindblog posts) that has persisted since Libet's original work showing motor cortex activity associated with a movement starts earlier than awareness of consciously willing that action.

Scenario 1: Consciousness controls actions:

You consciously decide what to do.
You do it.
You have conscious and unconscious knowledge of 2 and how it turned out.
Loop back to step 1.

Scenario 2: Consciousness does not control actions:

You unconsciously decide what to do.
You do it.
You have conscious knowledge (at least sometimes) of the results of 2.
The information in 3 is available to the unconscious parts of your brain.
Loop back to step 1.

I think most people agree that scenario 2 happens at all the time. For example, we usually don’t consciously think about walking or driving to work, or striking each key on a keyboard when writing an email. The question is whether scenario 1 ever happens.

But again my question is, does it matter? Look again at the sequences. What changes if scenario 1 or scenario 2 are happening? Isn’t consciousness still having a causal effect on actions in scenario 2, albeit a delayed one?

Maybe the real distinction is how often and how early step 3 in scenario 2 happens? I think there’s no question that it varies depending on the situation. I presented the scenarios above as two discrete possibilities, but I suspect the reality is more of a spectrum, with various actions arising with varying frequencies into consciousness.

An interesting pain suppression tactic.

Romano and Maravita report that magnifying the visual size of one׳s own hand modulates pain anticipation and perception, reducing experiened pain, a technique that might be exploited for practical use:

How to reduce pain is a fundamental clinical and experimental question. Acute pain is a complex experience which seems to emerge from the co-activation of two main processes, namely the nociceptive/discriminative analysis and the affective/cognitive evaluation of the painful stimulus.

Recently it has been found that pain threshold increases following the visual magnification of the body part targeted by the painful stimulation. This finding is compatible with the well-known notion that body representation and perceptual experience relay on complex, multisensory factors. However, the level of cognitive processing and the physiological mechanisms underlying this analgesic effect are still to be investigated.

In the present work we found that following the visual magnification of a body part, the Skin Conductance Responses (SCR), to an approaching painful stimulus increases before contact and decreases following the real stimulation, compared to the non-distorted view of the hand. By contrast, an unspecific SCR increase is found when the hand is visually shrunk. Moreover a reduction of subjective pain experience was found specifically for the magnified hand in explicit pain ratings.

These findings suggest that the visual increase of body size enhances the cognitive, anticipatory component of pain processing; such an anticipatory reaction reduces the response to the following contact with the noxious stimulus.

The present results support the idea that cognitive aspects of pain experience relay on the multisensory representation of the body, and that could be usefully exploited for inducing a significant reduction of subjective pain experience.

Practice and sleep form different aspects of skill.

Because I am a pianist I find this work by Song and Cohen totally fascinating. It conforms to my own experience in learning new note sequences in a piano composition (currently I'm working on Scriabin's Etude Op. 8 no. 12 D sharp minor). A fingering sequence that I find difficult I can discover to be playing in head during momentary waking during the night, and on the next day the notes come much more easily. Song and Cohen's distinction of transition and ordinal forms also matches with my experience of being able to verbalize (declarative memory) versus 'just knowing' (procedural memory) a passage.

Performance for skills such as a sequence of finger movements improves during sleep. This has widely been interpreted as evidence for a role of sleep in strengthening skill learning. Here we propose a different interpretation. We propose that practice and sleep form different aspects of skill. To show this, we train 80 subjects on a sequence of key-presses and test at different time points to determine the amount of skill stored in transition (that is, pressing ‘2’ after ‘3’ in ‘4-3-2-1’) and ordinal (that is, pressing ‘2’ in the third ordinal position in ‘4-3-2-1’) forms. We find transition representations improve with practice and ordinal representations improve during sleep. Further, whether subjects can verbalize the trained sequence affects the formation of ordinal but not transition representations. Verbal knowledge itself does not increase over sleep. Thus, sleep encodes different representations of memory than practice, and may mediate conversion of memories between declarative and procedural forms.

Using imagination or memory to increase prosocial behavior.

Gaesser and Schacter test two simple techniques for altering empathy towards the suffering of others, useful perhaps at the scale of individuals, but not obviously useful for large groups in opposition.

Empathy plays an important role in human social interaction. A multifaceted construct, empathy includes a prosocial motivation or intention to help others in need. Although humans are often willing to help others in need, at times (e.g., during intergroup conflict), empathic responses are diminished or absent. Research examining the cognitive mechanisms underlying prosocial tendencies has focused on the facilitating roles of perspective taking and emotion sharing but has not previously elucidated the contributions of episodic simulation and memory to facilitating prosocial intentions. Here, we investigated whether humans’ ability to construct episodes by vividly imagining (episodic simulation) or remembering (episodic memory) specific events also supports a willingness to help others. Three experiments provide evidence that, when participants were presented with a situation depicting another person’s plight, the act of imagining an event of helping the person or remembering a related past event of helping others increased prosocial intentions to help the present person in need, compared with various control conditions. We also report evidence suggesting that the vividness of constructed episodes—rather than simply heightened emotional reactions or degree of perspective taking—supports this effect. Our results shed light on a role that episodic simulation and memory can play in fostering empathy and begin to offer insight into the underlying mechanisms.

Exercise protects retinas.

Gretchen Reynolds points to an article by Lawson et al. showing that the increase in blood levels of brain-derived neurotrophic factors (B.N.D.F.), known to promote neuron health and growth, apparently also raises BNDF levels in the retina. In a mouse model for retinal degeneration (vaguely analogous to human macular degeneration), exercise that raises BNDF levels inhibits the retinal deterioration caused by brief (4 hour) exposure to very bright lights.

Aerobic exercise is a common intervention for rehabilitation of motor, and more recently, cognitive function. While the underlying mechanisms are complex, BDNF may mediate much of the beneficial effects of exercise to these neurons. We studied the effects of aerobic exercise on retinal neurons undergoing degeneration. We exercised wild-type BALB/c mice on a treadmill (10 m/min for 1 h) for 5 d/week or placed control mice on static treadmills. After 2 weeks of exercise, mice were exposed to either toxic bright light (10,000 lux) for 4 h to induce photoreceptor degeneration or maintenance dim light (25 lux). Bright light caused 75% loss of both retinal function and photoreceptor numbers. However, exercised mice exposed to bright light had 2 times greater retinal function and photoreceptor nuclei than inactive mice exposed to bright light. In addition, exercise increased retinal BDNF protein levels by 20% compared with inactive mice. Systemic injections of a BDNF tropomyosin-receptor-kinase (TrkB) receptor antagonist reduced retinal function and photoreceptor nuclei counts in exercised mice to inactive levels, effectively blocking the protective effects seen with aerobic exercise. The data suggest that aerobic exercise is neuroprotective for retinal degeneration and that this effect is mediated by BDNF signaling.

Another demonstration of the gender gap.

The observations of Brooks et al. are quite clear-cut:

We identify a profound and consistent gender gap in entrepreneurship, a central path to job creation, economic growth, and prosperity. Across a field setting (three entrepreneurial pitch competitions in the United States) and two controlled experiments, we find that investors prefer entrepreneurial pitches presented by male entrepreneurs compared with pitches presented by female entrepreneurs, even when the content of the pitch is the same. This effect is moderated by male physical attractiveness: attractive males are particularly persuasive, whereas physical attractiveness does not matter among female entrepreneurs. These findings fundamentally advance the science related to gender, physical attractiveness, psychological persuasion, bias, role expectations, and entrepreneurship.

Can body language be read more reliably by computers than by humans?

This post continues the thread started in my March 20 post "A debate on what faces can tell us." Enormous effort and expense has gone into training security screeners to read body language in an effort to detect possible terrorists. John Tierney notes that there is no evidence that this effort at airports has accomplished much beyond inconveniencing tens of thousands of passengers a year. He points to more than 200 studies in which:

...people correctly identified liars only 47 percent of the time, less than chance. Their accuracy rate was higher, 61 percent, when it came to spotting truth tellers, but that still left their overall average, 54 percent, only slightly better than chance. Their accuracy was even lower in experiments when they couldn’t hear what was being said, and had to make a judgment based solely on watching the person’s body language.

A comment on the March 20 post noted work by UC San Diego researchers who have developed software that appears to be more successful than human decoders of facial movements because it more effectively follows dynamics of facial movements that are markers for voluntary versus involuntary underlying nerve mechanisms. Here are highlights and summary from Bartlett et al.:

Highlights

-Untrained human observers cannot differentiate faked from genuine pain expressions
-With training, human performance is above chance but remains poor
-A computer vision system distinguishes faked from genuine pain better than humans
-The system detected distinctive dynamic features of expression missed by humans

Summary

In highly social species such as humans, faces have evolved to convey rich information for social interaction, including expressions of emotions and pain. Two motor pathways control facial movement: a subcortical extrapyramidal motor system drives spontaneous facial expressions of felt emotions, and a cortical pyramidal motor system controls voluntary facial expressions. The pyramidal system enables humans to simulate facial expressions of emotions not actually experienced. Their simulation is so successful that they can deceive most observers. However, machine vision may be able to distinguish deceptive facial signals from genuine facial signals by identifying the subtle differences between pyramidally and extrapyramidally driven movements. Here, we show that human observers could not discriminate real expressions of pain from faked expressions of pain better than chance, and after training human observers, we improved accuracy to a modest 55%. However, a computer vision system that automatically measures facial movements and performs pattern recognition on those movements attained 85% accuracy. The machine system’s superiority is attributable to its ability to differentiate the dynamics of genuine expressions from faked expressions. Thus, by revealing the dynamics of facial action through machine vision systems, our approach has the potential to elucidate behavioral fingerprints of neural control systems involved in emotional signaling. In highly social species such as humans, faces have evolved to convey rich information for social interaction, including expressions of emotions and pain. Two motor pathways control facial movement: a subcortical extrapyramidal motor system drives spontaneous facial expressions of felt emotions, and a cortical pyramidal motor system controls voluntary facial expressions. The pyramidal system enables humans to simulate facial expressions of emotions not actually experienced. Their simulation is so successful that they can deceive most observers. However, machine vision may be able to distinguish deceptive facial signals from genuine facial signals by identifying the subtle differences between pyramidally and extrapyramidally driven movements. Here, we show that human observers could not discriminate real expressions of pain from faked expressions of pain better than chance, and after training human observers, we improved accuracy to a modest 55%. However, a computer vision system that automatically measures facial movements and performs pattern recognition on those movements attained 85% accuracy. The machine system’s superiority is attributable to its ability to differentiate the dynamics of genuine expressions from faked expressions. Thus, by revealing the dynamics of facial action through machine vision systems, our approach has the potential to elucidate behavioral fingerprints of neural control systems involved in emotional signaling.

Evolved music specific brain reward systems.

Perhaps the most plausible suggestion for why music is universal in human societies is that it plays a central role in emotional social signaling that could have promoted group cohesion. Clark et al. comment on new work by Mas-Herrero et al. who have now documented a group of healthy people who, while responding to typical rewarding stimuli, appear to have a specific musical anhedonia, deriving no pleasure from music even though perceiving it normally. They cannot experience the intensely pleasurable shivers down the spine or ‘chills’ that are specific to and reliably triggered by particular musical features like the resolution of tonal ambiguity. These activate a distributed brain network including phylogenetically ancient limbic, stratal and midbrain structures also engaged by cocaine and sex. Clips from Clark et al.:

The musical anhedonia found by Mas-Herreo et al. is specific for musical reward assignment, rather than attributable to any deficiency in perceiving or recognising music or musical emotions. It is rooted in reduced autonomic reactivity rather than simply cognitive mislabelling. Moreover, it is not attributable to more general hedonic blunting, because musically anhedonic individuals show typical responses to other sources of biological and non-biological (monetary) reward. The most parsimonious interpretation of the new findings is that there are music-specific brain reward systems to which individuals show different levels of access….specific brain substrates for music coding … implies that these evolved in response to some biological imperative. But what might that have been?

The answer may lie in the kinds of puzzles that music helped our hominid ancestors to solve. Arguably the most complex, ambiguous and puzzling patterns we are routinely required to analyse are the mental states and motivations of other people, with clear implications for individual success in the social milieu. Music can model emotional mental states and failure to deduce such musical mental states correlates with catastrophic inter-personal disintegration in the paradigmatic acquired disorder of the human social brain, frontotemporal dementia …Furthermore, this music cognition deficit implicates cortical areas engaged in processing both musical reward and ‘theory of mind’ (our ability to infer the mental states of other people). Our hominid ancestors may have coded surrogate mental states in the socially relevant form of vocal sound patterns. By allowing social routines to be abstracted, rehearsed and potentially modified without the substantial cost of enacting the corresponding scenarios, such coding may have provided an evolutionary mechanism by which specific brain linkages assigned biological reward value to precursors of music.

These new insights into musical anhedonia raise many intriguing further questions. What is its neuroanatomical basis? The strong prediction would lie with mesolimbic dopaminergic circuitry, but functional neuroimaging support is sorely needed.

Here is the summary from the Mas-Herrero paper:

Music has been present in all human cultures since prehistory, although it is not associated with any apparent biological advantages (such as food, sex, etc.) or utility value (such as money). Nevertheless, music is ranked among the highest sources of pleasure, and its important role in our society and culture has led to the assumption that the ability of music to induce pleasure is universal. However, this assumption has never been empirically tested. In the present report, we identified a group of healthy individuals without depression or generalized anhedonia who showed reduced behavioral pleasure ratings and no autonomic responses to pleasurable music, despite having normal musical perception capacities. These persons showed preserved behavioral and physiological responses to monetary reward, indicating that the low sensitivity to music was not due to a global hypofunction of the reward network. These results point to the existence of specific musical anhedonia and suggest that there may be individual differences in access to the reward system.

Mechanism of muscle decay on aging, and its reversal.

Humans in their 70's and 80's experience a loss of skeletal muscle mass and strength (sarcopenia) that correlates with an increase in mortality in older populations. One reason this loss occurs is because the regenerative capacity of muscle stem cells (called satellite cells) declines with age as they switch from a quiescent state (from which they can emerge to generate new muscle progenitor cells) to a senescent-like state, which impairs the regeneration process, including activation, proliferation and self-renewal. Sousa-Victor et al. report, in experiments on aging mice, that this switch is caused by derepression of the gene encoding p16INK4a, a regulator of cellular senescence.  They find that genetically silencing p16INK4a in geriatric satellite cells restores quiescence and muscle regenerative functions, suggesting a possible clinical strategy for rejuvenating satellite cells.  I pass on this graphical summary of their results from the review by Li and Belmonte, followed by the abstract of their article.

Legend:

a. Satellite cells, a type of muscle stem cell, remain quiescent under normal conditions. After muscle damage, satellite cells become activated and re-enter the cell cycle to produce muscle progenitor cells that regenerate new muscle fibres. They also self-renew to replenish the stem-cell population. b, Sousa-Victor et al.3 report that during ageing, geriatric satellite cells lose their reversible quiescent state owing to derepression of the gene encoding p16INK4a, a regulator of cellular senescence. Instead, they adopt a senescent-like state (becoming pre-senescent cells), which impairs the regeneration process, including activation, proliferation and self-renewal.

Abstract:

Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with ageing. Here we report that geriatric satellite cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and that this irreversibly affects their intrinsic regenerative and self-renewal capacities. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, undergoing accelerated entry into a full senescence state (geroconversion), even in a youthful environment. p16INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions. Our results demonstrate that maintenance of quiescence in adult life depends on the active repression of senescence pathways. As p16INK4a is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.

Our lives are a concept, not a reality.

It is useful to occasionally be reminded of our essential strangeness, something I attempted in my "I-Illusion" web/lecture some years ago. Associate Scientific American editor Ferris Jabr engages this strangeness in his brief essay "Why nothing is truly alive". He notes the amazing life-like moving sculptures of Dutch artist Theo Jansen (see video), and points out how attempts to define life - as NASA has tried in defining the goal of what a search for extra-terrestrial life would look for - have floundered, the simple point being that while the concept of life sometimes has its pragmatic value for our particular human purposes, it does not reflect the reality of the universe outside the mind. Life is a concept, not a reality.

To better understand this argument, it’s helpful to distinguish between mental models and pure concepts. Sometimes the brain creates a representation of a thing: light bounces off a pine tree and into our eyes; molecules waft from its needles and ping neurons in our nose; the brain instantly weaves together these sensations with our memories to create a mental model of that tree. Other times the brain develops a pure concept based on observations — a useful way of thinking about the world. Our idealized notion of “a tree” is a pure concept. There is no such thing as “a tree” in the world outside the mind...Likewise, “life” is an idea. We find it useful to think of some things as alive and others as inanimate, but this division exists only in our heads.

Recognizing life as a concept is, in many ways, liberating. We do not need to recoil from our impulse to endow Mr. Jansen’s sculptures with “life” because they move on their own. The real reason Strandbeest enchant us is the same reason that any so-called “living thing” fascinates us: not because it is “alive,” but because it is so complex and, in its complexity, beautiful.

Restoring mitochondrial dysfunction associated with aging.

The aging of our bodies is by definition cellular aging, and it is hard to keep track with all the theories on why cells age. One of the most venerable models is that increasing damage to energy producing mitochondria in cells is a fundamental cause of cell decay and death. Mitochondrial energy production is accompanied by a low level of the aberrant production of reactive oxygen species (ROS) that damage mitochondria DNA and proteins. Another model suggested by Sinclair and colleagues is that alterations in nuclear gene expression due to reduced activity of the deacetylase SIRT1 may be the culprit. (SIRT1 is the enzyme linked to the anti-aging activity of resveratrol). Increasing this activity by increasing NAD+ (the energy coenzyme Nicotine Adenine Dinucleotide) levels can reverse age-dependent mitochondrial dysfunction. Here are highlights and the summary of their article.

Highlights

-A specific decline in mitochondrially encoded genes occurs during aging in muscle
-Nuclear NAD+ levels regulate mitochondrial homeostasis independently of PGC-1α/β
-Declining NAD+ during aging causes pseudohypoxia, which disrupts OXPHOS function
-Raising nuclear NAD+ in old mice reverses pseudohypoxia and metabolic dysfunction

Summary

Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD+ and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.