Bay area aging meeting summary

In the second Bay Area Aging Meeting, held at Stanford on December 4, 2010, research was presented regarding attempts to further elucidate and characterize the processes of aging, primarily in model organisms such as yeast, C. elegans (worms), and mice. A detailed summary of the sessions is available here. The work spanned some repeating themes in aging research:

Theme: processes work in younger organisms but not in older organisms
A common theme in aging is that processes function well in the first half of an organism’s life, then break-down in the second half, particularly the last 20% of the lifespan. In one example, visualizations and animations were created from the 3D tissue-sectioning of the intestine of young (4 days old) and old (20 days old) C. elegans. In the younger worms, nuclei and cells were homogenous and regularly spaced over the course of the intestine running down the length of the worm. In older worms, nuclei disappeared (an initial 30 sometimes ultimately dropped to 10), and the intestine became twisted and alternately shrunken and convoluted due to DNA accumulation and bacterial build-up.

Theme: metabolism and oxidation critically influence aging processes
Two interesting talks concerned UCP2 (mitochondrial uncoupling protein 2), an enzyme which reduces the rate of ATP synthesis and regulates bioenergy balance. UCP2 and UCP3 have an important but not yet fully understood role in regulating ROS (reactive oxygen species) and overall metabolic function, possibly by allowing protons to enter the mitochondria without oxidative phosphorylation. The mechanism was explored in results that worm lifespan was extended by inserting zebrafish UCP2 genes (not natively present in the worm).

Theme: immune system becomes compromised in older organisms
Two talks addressed the issue of immune system compromise. One team created a predictive analysis that could be used to assess an individual’s immune profile and potential response to vaccines by evaluating demographics, chronic infection status, gene expression data, cytokine levels, and cell subset function. Other work looked into the specific mechanisms that may degrade immune systems in older organisms. SIRT1 (an enzyme related to cell regulation) levels decline with age. This leads to the instable acetylation of transcription factor FoxP3 (a gene involved in immune system response), which suppresses the immune system by reducing regulatory T cell (Treg) differentiation to respond to pathogens.

Theme: systems-level understanding of aging processes
Many aging processes are systemic in nature with complex branching pathways and unclear causality. Research was presented regarding two areas: p53 pathway initiation and amyloid beta plaque generation. P53 is a critical tumor suppressor protein controlling many processes related to aging and cell maintenance: cell division, apoptosis, and senescence, and is estimated to be mutated in 50% of cancers. Research suggested that more clues for understanding the multifactorial p53 pathway could come from SnoN, which may be an alternative mechanism for activating p53 as part of cellular stress response. Neurodegenerative pathologies such as Alzheimer’s disease remain unsolved problems in aging. For example, it is not known if the amyloid beta plaques that arise are causal, or a protection mechanism in response to other causal agents. Some research looked at where amyloid beta is produced in cells, finding that after the amyloid precursor protein (APP) leaves the endosome, both the Golgi and a related recycling complex may be related in the generation of amyloid beta.

Theme: lack of conservation progressing up the model organism chain
Aging and other biological processes become more complicated with progression up the chain of model organisms. What works in yeast and worms may not work in mice, and what works in mice and rats may not work in humans. Some interesting research looked at ribosomal proteins, whose deletion is known to extend lifespan in model organisms. The key points were first that there was fairly little (perhaps less than 20%) overlap in lifespan-extending ribosomal protein deletions conserved between yeast and worms. Second, an examination of some of the shared deletions in mice (especially RPL19, 22, and 29) found some conservation (e.g.; RPL29), and also underlined the systemic-nature of biology, finding that other homologous genes (e.g.; RPL22L (“-like”)) may compensate for the deletion, and thereby not extend lifespan.

Theme: trade-offs is a key dynamic of aging processes
The idea of trade-offs is another common theme in aging; the trade-offs between processes, resource consumption, and selection. Exemplar of this was research showing that the deletion of a single gene involved in lipid synthesis, DGAT1, is beneficial and promotes longevity in mice when calories are abundant, but is also crucial for survival in calorie restricted situations. This supports the use of directed methylation to turn genes on and off in different situations. More details were presented in a second area of trade-offs: reproduction-lifespan. It is known that reproduction is costly and organisms without reproductive mechanisms may have extended lifespans. Research examined the specific pathways, finding that Wnt and steroid hormone signaling in germline and somatic reproductive tissues influenced worm longevity, particularly through non-canonical (e.g.; not the usual) pathways by involving signaling components MOM-2/Wnt and WRM-1/beta-catenin.

Conclusion
Academic aging research is continually making progress in the painstaking characterization of specific biological phenomena in model organisms, however the question naturally arises as to when and how the findings may be applied in humans for improving lifespan and healthspan. In fact there is a fair degree of activity in applied human aging research. Just as more individuals are starting to include genomic medicine, preventive medicine, and baseline wellness marker measurement in health self-management, so too are they consulting with longevity doctors. One challenge is that at present it is incumbent on individuals to independently research doctors and treatments. Hopefully in the future there could be a standard list of the anti-aging therapies that longevity doctors would typically offer. Meanwhile, one significant way for an individual to start taking action is by self-tracking: measuring a variety of biomarkers, for example annual blood tests, and exercise, weight, nutritional intake, supplements, and sleep on a more frequent basis.

Multiworld ethics and infinitarian paralysis

In an interesting 2008 essay (The Infinitarian Challenge to Aggregative Ethics), Oxford futurist scholar Nick Bostrom considers some of the issues that may arise in multiworld ethics. The central focus is on the theme of infinitarian paralysis, that individuals may not act since they think their impact is too small to matter. This is not a new theme; a classic example is not voting thinking that one voice does not matter. However, when considered in an infinite multiworld sense where every permutation of every individual and their actions exists elsewhere, perhaps individual voices really do not matter…and individual agents in any world could experience infinitarian paralysis.

As the essay suggests, humans may be able to qualify and circumscribe the issue of infinitarian paralysis and live and act unconcernedly in the current world. While this may be possible now, as humans become more rational through augmentation, and with the potential advent of artificial intelligence and hybrid beings, the specter of infinitarian paralysis may be harder to ignore. The inherent irrationality of humans together with the skill of ubiquitous rationalization is part of the cohesion of modern society. However, in a post-scarcity economy for material goods where the more immediate exigencies of living in the current world have evaporated, and biologically-derived utility functions have been re-designed, philosophical inconsistencies could well occupy a higher level of concern for thought-driven beings.

Evolutionary adaptations and artificial intelligence

Art and religion are human evolutionary adaptations. Are there similar evolutionary adaptations that human-level and beyond artificial intelligence would be likely to make? Another way to ask this is whether art and religion were predictable? It seems that they were, maybe not the detailed outcomes, but that mechanisms would arise to allow for the achievement of human objectives such as status-garnering and mate selection.

Likewise, it seems quite possible that human-level and beyond artificial intelligence would be likely to make evolutionary adaptations. Utility functions could be edited in many ways. The primary area could be performance optimization, continuously improving cognition and other operations. A second area could be related to societal objectives to the extent that artificial intelligence is present in communities. Artificial intelligence might not have art and religion, but could have related mechanisms for achieving external and internal purposes.

Cognitive enhancement through longer Schwann cells

Do faster thinkers have longer Schwann cells? Evolution has optimized human brain signal transmission in the existing machinery. Schwann cells (nerve cells) are punctuated with Nodes of Ranvier, unwrapped spaces that occur regularly on axons between the myelin sheaths that wrap and insulate the axons. The Nodes of Ranvier make signal transmission faster and conserve energy.

While Schwann cells may be the minimal length for the selection processes of evolution, they may not be optimized for modern thought. In many cases, modern thought constitutes more reasoning, imagining, conceptualizing, and contemplation than fight or flight responses. Different brain patterns arise from the different kinds of thought. One path to cognitive enhancement could be lengthening Schwann cells for faster transmission and possibly faster cognition.

Human body 2.0

The human body is a complex intricate composite of millions of years of evolution, but even the most cursory review immediately suggests the potential benefits of redesign. Without considering the deep possibilities and eventual exigencies of augmentation, it might be possible to replicate the full existing functionality of a human in a much smaller energy-conscious form factor, perhaps 1/10 the current size.

Waste: materials generation and energy expenditure
The biggest theme is waste due to untargeted processes. The main forms of waste are excess materials generated and energy used to move them around, all of which require a big overall system. Unlike the latest drugs, most natural molecules are untargeted; they travel around the body until they bump into a place to bind or are expelled unused. It is not just waste running through the blood stream and circulatory system, for example, steroid hormones diffuse into all cells, only binding to a small number.

Optimizing systems without sacrificing functionality
It could be argued that there are benefits to redundancy and waste could be better in some systems than others, for example, the value of having an extensive immune system on patrol 24/7 even though unused cell turnover is high. However, optimization could likely improve all system parameters.

Redesign phases: improved targeting and receptor enhancement
A potential human body redesign would certainly occur in phases, revising a few lower-impact operations first, targeting certain small classes of proteins to existing receptors for example. A second phase could include the generation or specificity-enhancement of receptors for a finer resolution of targeting.

Eventually, with robust targeting, it might be possible for the body to pump around 90% less ‘stuff.’

This would imply tremendous energy savings, and in turn decreased requirements for fluid, nourishment, vitamin, and mineral intake, and could even slow aging as processes do not wear out as fast.

Form factor hybrids
A smaller form factor may be undesirable for many reasons, but presumably it would be possible for streamlined wetware systems to merge into different kinds of hybrid form factors with ultralight ultrastrong hardware.

Synbio in space

Many interesting applications of synthetic biology in space missions were discussed at the Synthetic Biology workshop held October 30-31, 2010 at NASA Ames in conjunction with the National Academies Keck Futures Initiative. Scientists from a variety of backgrounds came together to brainstorm solutions in an integrative approach. The most impressive aspect was how different areas of synthetic biology have been progressing enough to discuss ideas and techniques that could be applied to space missions in a robust way.

Environment enhancement
One of the most important areas that synthetic biology may be able to help with is in making space environments more manageable and habitable by humans. The regolith, the powdery blanket covering the moon and Mars, may likely need to be ameliorated into harder less dusty surfaces.

Biomining
Synthetic biology could be helpful in creating microbes to faster weather regolith/rock for an order of magnitude quicker release of bioessential elements such as Magnesium, Calcium, Potassium, and Iron. (related publications)

Biomaterials and self-building habitats
Synthetic biology could help to create microbes for use in building structures, both as scaffolds and by growing on scaffolds. Bacterially-generated alternatives to Portland cement (bricks made from bacteria, sand, calcium chloride, and urea) are currently being investigated, along with other plant-development inspired architectures.

New gene function
While the discovery of new mammalian genes has become saturated, the majority of newly sequenced ocean-based microbes continue to have novel gene functions. Some of these may be quite useful in space environments, for example, D. radiodurans, which can withstand significant radiation and rebuild its DNA when damaged.

Space economics – the Basalt Economy
The economics of space suggest that synthetic biological solutions might be developed more readily for space challenges, and later deployed on Earth as the technologies mature. The main constraint for space is developing in-situ solutions that are cheaper than lifting materials from Earth, as opposed to creating competitive products for Earth-based supply chains (e.g.; synthetic biofuel).

Tools
Whole human genome and metabiome sequencing, genome synthesis and assembly, and genetic design and proofing software (bioCAD) as shown in Figure 1 are all improving. A vast industry similar to that of semiconductor design and manufacture could likely develop for synthetic biology.

Figure 1: Example of SLIC/Gibson/CPEC gene sequence assembly (Source)

Future of fashion

A new idea, spray-painted clothing, joins digital textile printing and 3-D printed clothing as a possible tool for creating the future of fashion.

Spanish fashion designer Manel Torres, working together with scientists from University College London, has developed spray-on fabric (Figure 1). Short fibers of wool, linen or acrylic are mixed with a polymer solvent which binds immediately as they are sprayed onto a person or mannequin.

Figure 1: Spray-on Fabric developed by designed Manel Torres (Source)

Clothing made from spray-on fabric was presented at the Science in Style fashion show, September 21, 2010 in London (Figure 2).

Figure 2: Science in Style, London, September 21, 2010 (Source)

There are many speculations about the wide range of potential applications for spray-on fabric. Some of the obvious ideas for on-demand fabric are sterile bandages and military and crisis relief use. Practical uses are interesting too. For example, to the extent the material is recyclable and cost-effective, being able to spray-on additional layers when feeling cold, and easily remove and discard them when hot could be quite convenient. Rain gear could be similarly donned and discarded. The long-expected futurist’s dream of on-demand 3D clothing printing booths could be closer to being realized.

Phase transition in intelligence

There could be at least three approaches to the long-term future of intelligence: engineering life into technology, simulated intelligence, and artificial intelligence. Further, while the story of evolutionary history is the domination of one form of intelligence, the future could hold ecosystems with multiple kinds of intelligence, particular specialized by purpose/task.

There are significant technical hurdles in executing simulated intelligence and artificial intelligence, but the areas have been progressing in Moore’s Law fashion. The engineering of life into technology will need to proceed expediently to keep pace with technological advance, and tie a lot of wetware loose ends together.

At present, the mutation rate of genetic replication puts an upward bound on how complex biological organisms can be. The human cannot be more than about 10x as complex as Drosophila (the fruit fly), for example. However, if the error rate in the genetic replication machinery could be improved, maybe it would be possible to have organisms 10x more complex than humans, and so on, and so on…

Consumer genomic testing update

In the wake of expected industry-wide regulation of consumer genomic testing, two of the big four testing companies, Navigenics and Pathway Genomics, have pulled their direct-to-consumer offerings in the last few months. Now a doctor must order their tests.

23andMe and deCODEme still have consumer genomic tests available, covering 174 conditions for $429 and 49 conditions for $2,000, respectively (Figure 1). Sooner rather than later could be a good time to sign up for a genomic service, possibly using year-end HSA dollars.

Figure 1. Landscape of direct-to-consumer genomic testing services.

Source: DNA Testing: Living Longer Via Personal Genomics

The potential industry-wide regulation is in regard to two issues, one is whether a physician must order the tests, and two, whether companies should be able to publish their interpretations of the results.

The DIYgenomics website lists two online petitions in support of rights to one's own genetic data:

• Petition for Access to Genetic Information

• Petition for Health Data Rights

Hardware apps (smartphone peripherals)

Apps are not just software anymore! The interesting new field of hardware apps, or smartphone peripherals, is under development.

One example is the iPhly iPhone-based radio controller. Radar detectors and dashboard car-surveillance cams could follow. Earthquake sensors are another obvious application, as accelerometer chips for sensing earthquakes have already been used in laptops.

Miniaturized modules could snap onto smartphones for many different applications. Scientific instruments could be an interesting application area, giving any individual the opportunity to have a mobile lab. Ultrasound and portable microscopes have already been demonstrated (iPhone attachment, cell phone attachment).

Portable personal sensing modules for biodefense (iPhone biodefense app spec) and health optimization could be a killer app. Microneedle arrays could continuously or periodically perform a sampling of hundreds of blood-based data points like Orsense does for continuous glucose monitoring. Mass spectrometer attachments could identify any substance chemically. Miniaturized genome sequencers and RNA sequencers could identify the underlying DNA and expression profiles of samples.