Future of Life Sciences: Top 10 List

The next wave of the biotechnology revolution is underway and promises to reshape the world in ways even more transformative than the agricultural, industrial, and information revolutions that preceded it.

It is not unimaginable that at some point, all biological processes, human and otherwise, could be understood and managed directly.

Here is a top ten list of key areas of contemporary advance in life sciences:

1. Synthetic Biology and Biotechnology 
2. Regenerative Medicine and 3D Printing 
3. Genomics, “Omics,” and Preventive Medicine 
4. Neuroscience 
5. Nanotechnology 
6. Big Health Data and Information Visualization 
7. Quantified Self (QS), Wearable Computing, and the Internet-of-Things (IOT) 
8. DIYscience, Citizen Science, Participatory Health, and Collective Intelligence 
9. Aging, Rejuvenation, Health Extension, and Robotics 
10. Space 

More information: Slideshare talk from the Max Planck Institute

Genetic and environmental rejuvenation of aging stem cells

The Buck Institute for Research on Aging held a symposium on Stem Cell Research and Aging March 1-2, 2012 in Novato, California. A range of levels of talks were given by scientists in the field to an audience of approximately 100 people. Three of the overall themes included a focus on the commonality of systemic cellular processes in development, aging, and rejuvenation, the importance of intervention in middle age when pre-clinical conditions are already in effect (for example, synapse loss, and over/under-expressed transcriptional profiles), and some of the challenges encountered thus-far in human stem cell clinical trials. The stage of the research is still more focused on characterization in a variety of model organisms rather than translational intervention for humans. Two of the most interesting areas of presentation were epigenetics and neurodegenerative disease.

Epigenetics
Since a good definition distinguishing young and old cells is not yet available, it was suggested that a cell’s epigenetic state and transcriptional network could be used to determine cell age and measure the impact of rejuvenation interventions. The stem cell environment is a critical factor to stem cell health and operation, and it has been found that aging can be reversed by altering the stem cell environment. One technique uses heterochronic parabiosis (pairing older and younger cells together), where each cell takes on the expression profiles of other. Genes that are downregulated in aging are reexpressed when exposed to younger cells, and stem cells put in an old environment take cues and act old (e.g.; have different expression profiles and lose lineage fidelity). Other rejuvenation techniques involve manipulating the transcriptional network, the networks of small RNAs that regulate the stability of the stem cell niche, and function appropriately in younger cells but not in older cells. However, in addition to heterochronic parabiosis, muscle stem cells may be rejuvenated through transcriptional interventions such as overexpressing the protein upd, activating the notch gene, inhibiting the Wnt gene or the TGF-beta gene, and stimulating proteins secreted by embryonic stem cells. The good news is that given the right genetic and environmental clues, aging cell states may be reversed.

Neurodegenerative disease
Regarding neurodegenerative disease, there is a new understanding of human cortical neurogenesis; that it occurs in the outer sub-ventricular zone (OSVZ) as opposed to the ventricular region, which also may explain how so many cortical columns are generated. The results of a four-year NINDS-sponsored clinical trial injecting fetal brain stem cells into aged patients with Parkinson’s disease were discussed; that the outcome and side effects were discouraging. This type of trial might fare better in patients who did not already have the movement disorder dyskinesia and with an improved understanding of the biological mechanisms of the disease, and better cellular delivery methods. Also regarding Parkinson’s disease, synapse loss is already beginning in middle age; for example there may be a 60% synapse loss before the disease is detected. Pacemaker neurons degenerate synapses and then synapse loss degenerates soma (the cell body of neurons).

Longevity genomics paper retracted

On July 22, 2011, a high-profile longevity genomics paper published in Science in July 2010 was retracted. The paper, ‘Genetic Signatures of Exceptional Longevity in Humans,’ was the work of Thomas Perls and Paola Sebastiani (Boston University). The initial study had been revised per editorial concerns that arose last year, but has now been retracted possibly due to issues related to the replicatability the findings.

The revised study results were presented by the team at the American Aging Association meeting in June 2011. These data featured nine single SNP associations (versus two previously), and linked 281 SNPs to signatures for exceptional longevity (versus 180 SNPs previously). The overall conclusion remained unchanged - that

centenarians, while having the same disease mutational profiles as non-centenarians, have other specific aspects to their genetic profiles which indicate a signature for exceptional longevity

Practical applications in anti-aging

One nice aspect of aging conferences is that there are usually a few gems of information that can be applied immediately in humans. Several actionable solutions were highlighted at the 40th annual meeting of the American Aging Association held June 3-6, 2011 in Raleigh NC USA (conference summary), in the areas of pharmaceuticals, nutrition, lifestyle, exercise, and fasting.

In summary, hypertension drug losartan may help sarcopenia, the healthier fats and antioxidants in walnuts, blueberries, and nectarines may facilitate health, hot tubs may reduce blood pressure, endurance exercise is better for older adults, and protein restriction may be the best form of caloric restriction.

In detail...

• In pharmaceuticals, the prescription drug losartan (an angiotensin receptor blocker) is typically used to treat hypertension and high blood pressure. It may also have anti-aging benefits in combating sarcopenia and frailty by improving muscle remodeling and grip strength.

• In nutrition, recommendations were for walnuts, blueberries, and nectarines. Walnuts are good because they are the only nut containing a significant amount of alpha-linolenic acid (ALA), and because they are mainly composed of polyunsaturated fatty acids (PUFA, both omega-3 and omega-6) rather than monounsaturated fatty acids (MUFA), as most other nuts. Blueberries continue to be an important suggestion for anti-aging. They contain anthocyanins, antioxidants which may prevent inflammation and help to improve brain signals and memory function. The 2011 Blueberry Health Study reported that individual cognitive performance improved 1% over a one year period from consuming one half cup to two cups of blueberries per day. Necatrines (and acai) also have antioxidant properties and have been found to reduce oxidative damage and improve longevity in Drosophila melanogaster (Boyd, Free Radic Biol Med, 2011).

• A lifestyle anti-aging remedy was found in nonhuman primates. Heated hydrotherapy, e.g.; jacuzzis, two times a week for 30 minutes at 39-41 degrees C, induced heat shock response (which declines with age) and increased production of heat shock proteins 70 and 90 which resulted in reduced blood pressure.

• Exercise is always a good anti-aging improvement especially since 60% of U.S. adults over 60 have insufficient physical activity. Type II fibers (fast-twitch) are most vulnerable to aging so instead of trying to improve these, for older adults, it is better and easier to maintain Type I fibers associated with endurance exercise. For example, 70-80 year olds running 2-3 miles a few times a week had the glucoregulation profiles of sedentary adults in their 20s.
  

• Fasting, especially amino acid (e.g.; protein) deprivation, before chemotherapy and surgery was found to help in reducing injurious impact.

Conference report: interventional anti-aging

The focus of the 40th annual meeting of the American Aging Association held June 3-6, 2011 in Raleigh NC USA was emerging concepts in the mechanisms of aging.

Many usual topics in aging were covered such as dietary restriction (DR), inflammation, stress resistance, homeostasis and proteasome activity, sarcopenia, and neural degeneration.

Newer methods like microRNAs and genome sequencing were employed to investigate gene expression variance with aging and genetic signatures of longevity.

Aging as a field continues to mature including by using a systems approach to tracing conserved pathways across organisms, sharpening definitions of sarcopenia, frailty, and healthspan, and distinguishing interventions by age-tier (early-onset versus late-onset).

A pre-conference session on late-onset intervention concluded that there are numerous benefits to deriving such interventions.

Conference talks applied the biology of aging in a translational manner to intervention development.

• Using an individual’s own stem cells to regenerate organs for transplantation and as a cell source for cellular therapies could be a powerful near-term solution to disease.
  
• Several proposed interventions were pharmaceutical, myostatin inhibition, losartan, JAK pathway inhibitors, and enalapril for frailty and sarcopenia, and metformin to promote Nrf2 anti-inflammation response.
  
• In dietary restriction, protein restriction was found to be better than general calorie restriction. Short-term fasting may be helpful in chemotherapy, surgery, and acute stress, simultaneously increasing the killing of cancer cells by chemotherapy, while improving the survival of normal cells.
  
• Immune system interventions remain elusive, although statins may help to improve cellular-senescence promoted bacterial infection.
  
• Engineered enzymes may be useful in lysosomal catabolism.
  
• Dietary restriction mimetics, most promisingly involving TOR (TORC1 inhibition and rapamycin), may be more feasible than dietary restriction.

More details: Meeting Summary preprint.

Anti-aging research developments in rapamycin, sirtuins, and stem cells

The Third Bay Area Aging meeting was held at Berkeley on May 8, 2010.

One highlight was the emperor’s new clothes statement “Maybe C. Elegans (e.g.; worm) is not the correct model organism for human aging!”

A variety of research was presented, with four themes amongst the most interesting:

1. Role of rapamycin in preventing inflammation
Rapamycin (more technically known as the mammalian target of rapamycin (mTOR)), has long been examined in aging since it is a protein that regulates a range of cellular behavior including growth, proliferation, motility, and survival. Initially hoped to be useful in treating cancer, rapamycin later turned out not to kill tumors due to systems biology; when mTOR is given and the TOR pathway is knocked out, the ERK pathway is upregulated instead.

However new research presented by Remi-Martin Laberge (Buck) shows that there is hope for rapamycin in the context of inflammation prevention. The normal process is that DNA damage response leads to NF-kB (a protein controlling DNA transcription) activation which leads to IL-6/8 (inflammation-related proteins) buildup, but with an mTOR introduction of rapamycin, instead IL-1a (an immune-response regulator) is obtained which prevents inflammation.

The prevention of inflammation is thought to be critical in anti-aging as many aging pathologies start with inflammation which later escalates to waste-build up and tissue break-down. This work is part of ongoing SASP (senescence-associated secretory phenotype) research by the Campisi lab (recent papers on p53 and p38MAPK).

2. Role of recently discovered SIRT7 in oncogenesis
Matt Barber (Stanford) presented work regarding a recently discovered SIRT (Silent Information Regulator) protein. SIRT7 is a chromatin-associated protein and site-specific histone H3 K18 deacetylase. There is a potential connection with SIRT7 and oncogenesis in that SIRT7 interacts with ELK4 (a pathway upregulated in cancer) to suppress a tumor suppressive gene expression network and helps stabilize aggressive cancer phenotypes.

3. Enhanced stem cell therapies
Randy Ashton (Berkeley) showed research regarding the increased ability to dopaminergiacally pattern hESCs to facilitate regenerative therapies for Parkinson’s disease. This was accomplished by making a protein important in neural development, sonic hedgehog, more sensitive through polyvalency.

4. Protein homeostasis and proteasome activity necessary for long lifespan
Brett Robison (Buck) presented work suggesting that normal proteasome function is required for full lifespan in yeast. The proteasome is an important location for waste degradation in cells. Aging cells showed impaired protein homeostasis and decreased proteasome function but it is unclear if this is cause or effect. Theodore Peters (Buck) also showed that maintaining protein homeostasis is important for healthy aging.

Mitochondrial motility tied to neurodegenerative disease

New research suggests some details of how damaged mitochondria may be responsible for Parkinson’s disease, Alzheimer’s disease, and aging.

Mitochondria are the energy powerhouse of the cell. They are managed and distributed via a mitochondrial transport complex involving proteins Miro and Milton which have KHC (kinesin heavy chain), EF hands, and GTPase domains. A pathway related to the functioning of the complex regulates mitochondrial motility through calcium concentration: the higher the level of cytosolic calcium, the lower the mitochondrial motility. Motility is reversibly altered as necessary to meet the energy requirements of any cell, including neurons.

Part of this same mechanism may be used by Parkinson’s genes Pink1 and Parkin to bind to the mitochondrial transport complex to permanently inhibit mitochondrial motility, thus blocking dopaminergic neurons.

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.

Aging research: systems biology, genomics and new tools

Three important themes emerged from the Buck Institute’s Systems Biology Symposium of Aging held November 10-13, 2009. The themes were progress in the overall understanding of aging as a systems biology problem, the role of genomics in aging, and new tools development for aging research. Happily, some immediately applicable tidbits were discussed: the findings of the protective response of endurance exercise, and the use of resistance exercise as a countermeasure to sarcopenia. (Mark Tarnopolsky)

Theme 1: Aging is a systems biology problem
Inflammation
Increasingly, aging is being understood as a systems biology problem involving cascades of signals across multiple pathways, many of which break down with aging. In younger organisms, problems are managed automatically as they arise, but in older organisms, the resolution processes do not work as well. When cells become damaged as a consequence of aging, they can either self-destruct through apoptosis (regulated cell death) or become senescent (living on without dividing). Senescent cells persist in tissues, where they may secrete inflammatory proteins. Many major age-related diseases, including atherosclerosis, heart attack, stroke and metabolic syndrome, share an inflammatory pathogenesis. The build-up of senescent cells can lead to both degenerative disease (aging) and hyper-proliferative disease (cancer). There are some efforts underway to facilitate the removal of senescent cells, for example, using an MMP inhibitor to kill senescent cells.

Dynamic regulatory continua
It is being suggested that more and more aspects of living systems such as humans are dynamic regulatory continua, and that there may be optimum points on the continuum which become harder to maintain with aging. One example of a dynamic regulatory continuum is the interrelation of cholesterol, fats, and Alzheimer’s disease. Having lower levels of the 142 alpha-beta plaques is neuroprotective, for example, but higher levels become harmful. One technique for understanding dynamic regulatory continua is to look at explaining the events at one biological level in terms of the events at the levels above and below them. (John Tower)

Signaling pathways
There is more of an effort to examine whole processes such as pathway networks and the chain of events in DNA transcription and translation. Current knowledge of signaling pathways is fairly primitive. The role of mRNA translation is being investigated as it is known to be related to growth promoting activities like cancer. There is the general translation of RNA, but this can be further modulated by the cell. In addition, signaling pathways are not working alone, there are probably many pathways converging. For example, there is likely cross-talk between several important signaling pathways such as the insulin pathway, the TGF-beta pathway, the IGF-1 pathway, and the TOR pathway. (Heidi Tissenbaum) In another example of the systemic interactions of aging, amyloid-binding compounds were found to suppress protein aggregation models in concert with homeostatic function (i.e., autophagy, chaperones, etc.). (Gordon Lithgow)

Theme 2: The role of genomics in aging
As with many areas of biology and medicine, the role of genomics is becoming increasingly important in aging. While it is known that there is little variation (0.1%) among SNPs in human genomes, 12% of the genome may vary structurally (copy-number variations, deletions, inversions and insertions of genes). On the threshold of whole human genome sequencing, it is being realized that SNP data alone is insufficient for a genomic understanding of health; more levels of data and annotated data, potentially including RNA sequencing to see protein expression will be needed. (Mike Snyder)

Variation in genomes
Three areas of research were presented regarding genome variation and aging. First were the long-expected results of Boston University's genome-wide association study (GWAS) on centenarians. The study found 150 SNPs in the genetic signature of longevity, 33 of which meet genome wide significance and are replicated. The most important longevity genes, most already associated with aging pathways, were: IL7 (immune system), CDKN2B (tumor suppressor), and APOE, CTNNA3, TOMM40, SORCS1, and SORCS2 (Alzheimer’s disease). (Tom Perls)

Related results were confirmed by personal genomics company 23andme. A study of senior athletes found that this cohort exhibited lower risk than the database in general. Ten chronic disease conditions were reviewed including coronary artery disease, breast cancer, prostate cancer, heart attack, type 2 diabetes, high blood pressure, high cholesterol, and macular degeneration. (Joanna Mountain) However, other research found that there is not a full overlap between genes conferring longevity and genes conferring increased healthspan. (Monica Driscoll)

Variation in genomic expression
Four interesting research findings found variation in genomic expression between older and younger organisms. First, another centenarian study found significant diversity of microbial communities in different age groups. For example, there was a high level of expression of certain miRNAs in older livers (miRNA-200c, miRNA-141, and miRNA-31). (Claudio Franceschi) A second study found that a full third of genome expression changed with age in worms. (Simon Melov)

A third study found a general relaxation in translational control and protein production during aging. It was proposed that increased or sloppy protein expression might contribute to proteotoxicity. (Monica Driscoll) Applying a systems biology and network analysis approach, a fourth study looked at how the structure of biological networks declines with age. The AGEMAP (a gene expression database for aging in mice) was reviewed, finding 26% fewer edges (edge nodes on the network) in 24 month old mice vs. 16 month old mice. It is possible that gene expression networks could lose integrity with age. An unexplored but possible explanation is that if there if less transcription, then network edges disappear. (Daniel Promislow)

Theme 3: New tools development for aging research
New approaches and tools are critical to advancing the study and potential remedy of aging, and three interesting talks were presented. First, progress in microfluidics and microscopy was discussed, particularly an exceptional development in electron microscopy that may allow the noninvasive molecular-resolution imaging of live samples (Figure 1). Usually electron microscopy is a destructive technique as the electron beam destroys the sample in the process of inspecting it. (paper: Noninvasive Electron Microscopy with Interaction-free Quantum Measurements). (Fatih Yanik)

Figure 1: In vivo noninvasive molecular imaging.

Image credit: http://www.rle.mit.edu/bbng

A second area of improvement has been in the targeted analysis of specific proteins. Now that there are robust measures for mRNA, proteins and post-translational modifications are the next areas of interest. Traditional shotgun analysis techniques are being improved upon by targeted analyses of specific proteins using mass spectrometry. The process is to take a protein mixture, produce peptides through proteolysis, collect a snapshot of multiple peptides at once, and use mass spectrometry to separate them by their mass. This method greatly expands protein identification and analysis capabilities, including the ability to do time course experiments. (Mike MacCoss)

Third, a genomic database tool, PharmGKB, was presented. The database facilitates a systems approach to pharmacology. Researchers can search for pharmacogenes, for example, given a drug and putative indication, ranking all genes in the genome for the likelihood of interactions. The database contains information regarding over 500 drugs, 500 diseases, and 700 genes with genotyped variants as of November 2009. (Russ Altman)

Progress in Aging: Secretome, mRNA and Nutrients

The U.S. National Institute on Aging held a Systems Biology of Human Aging conference in Baltimore, MD on December 8-9, 2009. Several interesting topics were considered including the complexities of modeling the process of aging, the role of RNA in gene regulation, neurodegenerative disease and vascular compromise, and gene expression and signaling networks.

Aging: break-down in signaling networks
Aging is a systems biology problem where signaling networks break down. As part of the signaling break down, senescent cells secrete inflammatory proteins which together can be thought of as the ‘secretome.’ Judy Campisi has found that the secretome, the senescence-associated secretory phenotype (SASP), can provide a common biological explanation for the related phenomena of aging, degenerative disease and cancer. Senescent cells produce the SASP, essentially inflammation, which can then trigger degenerative disease (aging) and hyper-prolific disease (cancer). A potential solution is to remove the 10-15% of senescent cells that are not naturally killed by the immune system. Some secretome research has been applied specifically to vascular smooth muscle cells which have the tendency to unhealthily proliferate and migrate with aging, in a process called the pro-inflammatory age associated arterial secretory phenotype (AAASP).

RNA and gene regulation
With mRNA analysis it is possible to obtain the transcriptome, the complement of DNA that has been synthesized into RNA and exists in a cell at any given time snapshot. This is starting to allow findings that the process of transcription and translation is probably more tightly coordinated than previously thought, and that translational control could be a dominant force in transcription. The norm is starting to be that RNA binding protein and non-coding mRNA expression should be identified too in analysis, not just protein expression. Generally, DNA is much more active than initially thought with perhaps 90% of the human genome being actively expressed in some cell of the body. The level of certain mRNAs can be an upstream pathway indicator of aging as mRNAs may increase or decrease with aging which can cause the level of damaging proteins to increase. For example, MKK4 increases with the overexpression of four mRNAs.

Alternate day fasting and nutrients
Alternate day fasting may potentially confer the same benefits as calorie restriction in animals and humans, both in physical and neurological health. Neurodegenerative disease and neurological decline are part of aging pathologies. A countermeasure may be to increase the levels of certain proteins, especially BDNF, brain-derived neurotrophic factor, which is neuroprotective, neurogenerative and important in plasticity and synaptic activity. Some nutrients that may help to increase BDNF levels are sulforphane (broccoli), curcumin (tumeric), catechins (green tea), allicin (garlic), hypericin (St. John’s Wort) and plumbagin.

MMP inhibitor to kill senescent cells

Important work in the understanding and remedy of aging at the Buck Institute’s Systems Biology Symposium of Aging held November 10-13, 2009 was presented by Judith Campisi in a keynote talk, “The Four Horsemen – Damage, Inflammation, Cancer and Aging: Integrating Aging and Age-Related Research.”

Summary
Campisi has found a common biological explanation for the related phenomena of aging, degenerative disease and cancer: the senescence-associated secretory phenotype (SASP). Senescent cells produce the SASP, essentially inflammation, which can then trigger degenerative disease (aging) and hyper-prolific disease (cancer). A potential solution is to remove the 10-15% of senescent cells that are not naturally killed by the immune system by using matrix metalloproteinase (MMP) inhibitors.

Background
Humans are much longer-lived than other organisms such as flies because they have evolved cell-dividing mechanisms for tissue regeneration and repair. However, mistakes in the form of mitotic mutations occur during this process and build-up cumulatively which can cause cancer. To counter the build-up of mutations, tumor suppressor mechanisms evolved. One action of gate-keeper tumor suppression mechanisms is to direct damaged cells to senesce, or lose function.

Senescent cells are not harmless, they amass at sites of inflammation and pre-cancer and secrete up to 40 different cytokines (immunoregulatory proteins) which together can be thought of as the SASP secretome. All major age-related diseases share an inflammatory pathogenesis including atherosclerosis, myocardial infarction, stroke and metabolic syndrome. The build-up of senescent cells can lead to both degenerative disease (aging) and hyper-proliferative disease (cancer).

The purpose of the cytokines is to repair tissue. In the SASP secretome, they are perhaps trying to summon the immune system, communicating to the rest of the tissue that there is a problem. The immune system does arrive and kill most senescent cells, but 10-15% survive, perhaps due to the over-expression of matrix metalloproteinases (MMPs) which can cleave the ligands off the cell surface where natural killer cells would bind, allowing the cell to escape the immune system.

Solution
Extending the existing research and application of matrix metalloproteinase (MMP) inhibitors, chemicals that mimic the binding site, Campisi’s lab has been able to drive senescent cell killing to 95%.

VC guide to anti-aging biotechnology investing

Several promising startup companies focused on the nascent but obviously significant and growing anti-aging biotechnology space were present or discussed with interest at the recent SENS4 (Strategies for Engineered Negligible Senescence) conference in Cambridge, U.K., September 3rd – 7th, 2009 (program) (full conference report).

1. Epeius Biotechnologies, San Marino, CA, USA: Rexin-G, a tumor-targeted injectable gene delivery system
2. FoldRx, Cambridge, MA, USA: small molecule therapeutics to treat protein misfolding diseases, and bind and clear undesired molecules
3. Gencia Corporation, Charlottesville, VA, USA: mitochondrial DNA rejuvenation using the rhTFAM (recombinant-human mitochondrial transcription factor A) protein
4. Genscient, Fountain Valley, CA, USA: novel chronic disease therapeutics by combining genomics and selective screening (a large Alzheimer’s Disease genetic study is in progress with Kronos and TGen)
5. Knome, Cambridge, MA, USA: whole human genome sequencing (consumer offering)
6. Neotropix, Malvern, PA, USA: oncolytic viruses for the treatment of solid tumors
7. Pentraxin Therapeutics Ltd, London, UK: small molecule drug CPHPC specifically targeting SAP (serum form of amyloid P) and removing it from the blood and brains of patients with Alzheimer’s Disease
8. Repeat Diagnostics, Vancouver, BC, Canada: telomere length measurement for total lymphocyte and granulocyte populations (consumer offering)
9. Retrotope, Los Altos Hills, CA, USA: using isotope effect to slow down damage pathways and control metabolic processes associated with oxidative stress
10. StemCor Systems, Inc., Menlo Park, CA, USA: bone marrow harvesting system
11. T.A. Sciences, New York, NY, USA: telomerase activation via the single molecule TA-65, licensed from Geron Corporation (consumer offering)
12. TriStem Corporation, London, UK: retrodifferentiation technology to create stem cells from mature adult cells

Aging is solvable

That aging is understandable and solvable, not necessarily immediately but ultimately, was one topic not seeing a lot of opposition at the American Aging Association (AGE) conference in Phoenix AZ May 29 – June 1, 2009. Key research highlights are below.

Aging is a key contemporary concern, on the order of climate change, as all countries worldwide have populations increasingly stratified towards aging. Aging is not just a medical condition but a key challenge to be resolved for advanced societies to be successful in the long-term. Productivity, healthcare costs and happiness and comfort could all be improved with advances in the remedy of aging. Aging has advanced from a nebulous concept to concrete mechanisms that can be understood and managed. Thematically, most of the bioparts impacted in aging (cells, genes, proteins, neurons, etc.) seem to still be present in older organisms, just not functioning the way they did when the organisms were younger, suggesting that it may be possible to manage and reverse aging processes, and confirming the systemic nature of aging including, for example, the role of a healthy microenvironment and cell-cell signaling. Reductionism as an approach has proved unsuccessful.

Aging is a multidisciplinary phenomenon, involving different deterioration processes in different tissues over time. Aging involves a variety of fields (immunology, cancer, regenerative medicine, cognition, micronutrients, etc.) and a variety of levels of research species (C. elegans (worms), Drosophila (flies), mice, rats and humans). At AGE, the organizational structure was a focus on systems pathways, particularly signaling and hormones, together with a look at the role of proteins in aging.

AGE was an excellent place to obtain a broad and deep comprehension of how aging works. The systemic rigor required to characterize the process-intensive nature of aging has been making significant progress, with a much more detailed understanding of the complex nested multifactor pathways now existing as compared with that of even a few years ago. It is clear that the painstaking characterization work could be further improved with automation and quantitative tools, especially for example, digital linkage of aging pathways across organisms.

As with other life sciences areas, the potential widespread quick and cheap availability of the sequencing of genomes, proteomes, etc. is likely to dramatically change how the science of aging is conducted, though not guarantee quick solutions. As pathways continue to be confirmed, they can be digitized into software and nearly indefinite simulated iterations could be run before conducting time-consuming and expensive bench experiments in confirmation.

Many interventions work for extending the lifespans and healthspans of lower order organisms, for example knocking out any one of 200 known genes may extend the lifespan of the C. elegans worm but the specifics and replicability of the mechanisms in higher order organisms are not known. It does not make sense to directly translate point solutions up to mammals given the systemic nature of the organisms and aging processes. Even moving one biomarker for alcohol consumption from monkeys to humans is not direct.

Exciting new research findings
Reference links below and conference abstracts here

1. 3-D organ printing: Use only biologics (cells and cell products) in a scaffold-free tissue engineering process to print 3-D tissues and organs which can be vascularized prior to implantation, relying on developmental biology to trigger the cells to fuse and self-assemble into organs. (Gabor Forgacs, video, lab, organ printing)
   
2. Stem cell antibodies: Improve existing cardiac stem cell therapies (only 1% of cells reach the intended destination) by using specific antibodies for better targeting and retention of stem cells at sites of tissue injury. Replace cardiomyocytes with adult stem cells. (Jim Larrick, paper, general information)
   
3. Stem cells: Amplify and rejuvenate adult stem cells for injection into knees and hips as an alternative to surgical replacements. (Regenexx)
   
4. Bioremediation: Use natural enzymes to remediate biological build-ups; cholesterol oxidase from Brevibacteria to reduce 7KC cholesterol in atherosclerosis and A2E-degrading enzymes to improve macular degeneration. (John Schloendorn, research program, paper)
   
5. Life extension: Examine the mechanisms of dietary restriction (DR) with further elucidation of TOR (target of rapamycin) pathways, a fast growing area of research. Find that inhibiting a downstream gene in the TOR pathway, HIF-1 (a transcription factor important for growth and metabolism), extends lifespan in worms. (Pankaj Kapahi, paper)
   
6. Life extension: Generate a 10x lifespan extension in C. elegans by silencing many components of insulin/IGF-1 signaling (IIS) possibly via the disruption of PIP3 (a key signaling molecule required for the membrane tethering of many signaling molecules). (Puneet Bharill, paper)
   
7. Amyloid plaque reduction: Use a known plaque imaging agent, ThT (Thioflavin T), as a therapeutic for amyloid plaques. (Silvestre Alavez, lab affiliation, paper)
   
8. Cancer protection: Find that naked mole rats have two layers of anti-cancer protection, humans have only one. p16 is the first-line-of-defense anti-cancer protection mechanism found in naked mole rats. Humans (and other organisms) also have p16 (a suite of three genes), perhaps the mechanism for its upregulation (probably a cell:cell signaling dynamic) in naked mole rats could be understood and turned on with an enzyme in humans. (Andrei Seluanov, earlier research)
   
9. Cognitive function: Find that neurogenesis is possible in aged organisms with exercise followed by cognitive stimulation (e.g.; tackling a puzzle or challenge); organisms can benefit by building up a larger reservoir of brain cells earlier in life by being exposed to a variety of external stimulation. (Gerd Kempermann) This author’s speculation: Perhaps neurogenesis could be further harnessed for brain enhancement beyond currently realizable human capacities as this mechanism is better understood.
   
10. Aging biomarkers: Upstream the aging focus to prevention by measuring biomarkers and introducing interventions. Some suggested biomarkers of aging are p16 gene levels (which can be decreased with exercise), telomere length, the level of senescent cells, and the number of circulating lymphocytes in the immune system (measure total T cells (CD3+), B cells (CD19+) and CD28 absolute numbers on CD8+ T cells). (Kronos research projects, test menu; telomere length measuring)
    
11. Hormones-IGF: Find no conclusive evidence of insulin-like growth factor's (IGF) ability to retard natural aging, though on an individual basis some people may find it useful. (Marc Blackman)
    
12. Hormones-HRT: Find that hormone replacement therapy (HRT) can be good for improving cognitive function and bone loss in women that do not have a risk of heart disease; HRT should be started with the onset of menopause, not later. (Barbara Sherwin, Eef Hogervorst)
    
13. Cost of reproduction: Find that ovary removal in grasshoppers resulted in a 25% increased lifespan, contributing to existing evidence regarding the high cost of reproduction. (John Hatle) This author’s speculation: In the farther future, in humans, it could be quite desirable to closely manage fertility, turning it on and off at will, if fertility is even necessary.
    
14. Micronutrients: Find tremendous nutritional benefits from the consumption of fruits with skin, especially blueberries (pterostilbene that reduces oxidative stress), blackberries, raspberries, red grapes, pomegranates, cranberries, plums, strawberries, cherries, pears and apples (phytochemicals that provide cancer prevention), walnuts (preventing the inflammation and oxidative stress of brain aging:), green tea (catechins that reduce cardivascular and cancer risk) and tempeh (fermented whole soy bean with folate is healthier than tofu (processed soy bean curd)). (Blueberries: Agnes Rimando, Rolf Martin; Apples: Rui Hai Liu, Walnuts: James A. Joseph, Green tea: Vojo Deretic, Tempeh: Eef Hogervorst)
    
15. Calorie restriction (CR)/dietary restriction (DR): Find that in humans, improved biomarkers for CR/DR, vegan and raw food diets that result in the extension of the onset of aging challenges. (John Holloszy)
    
16. Aging mice testbed: A mouse type that sufficiently recapitulates early aging, the human WS phenotype (Werner syndrome), has been created which could hasten mammalian aging research. (David Kipling)
    

Conclusion
Aging is a key contemporary issue. Research is advancing both incrementally and radically in every area of aging. The highest immediate impact could come from working on aging problems upstream at important fulcrum points that impact everything below them, such as genetics, epigenetics and the immune function. The research is progressing and it is starting to be time for VCs, big pharma and DIYbio’ers to take advantage of the many interesting and actionable possibilities.

Status of Research on Human Aging

Longevity is the new alternative energy
With $10m quickly raised by the Methuselah Foundation, VCs just beginning to see the opportunity and continually soaring healthcare costs, the longevity market could easily become as big as the alternative energy/climate change solutions market has become now.

Longevity research status
Grossly generalizing, the main focus in aging research is figuring out how to get processes that already occur, in the young and in cancer for example, to occur at other times, in the old. The optimum approach may include both reverse engineering and forward engineering in the form of synthetic biology as has been successful in other biological research areas like gene synthesis.

Aging is multidisciplinary, comprising at minimum the study of stem cells, immunology, cancer, DNA damage, tissue engineering, genetic engineering, regenerative medicine and micronutrients.

A comprehensive collection of anti-aging research findings was presented at the Aging 2008 conference June 27-29 at UCLA. The current developmental stage of aging research is early, perhaps in the second inning. Groundwork is being laid, phenomena are being documented, understanding of general mechanisms is sought, existing processes are being enumerated and early cycles of testing have begun primarily on flies and mice.

The seven primary causes of aging are DNA mutations in the cell nucleus and mitochondria, junk that builds up inside and outside cells, cells sticking together and cell loss and death. These are described at length, together with potential solutions, in aging research pioneer Aubrey de Grey’s book, Ending Aging and in the journal Rejuvenation Research. De Grey’s organization, the Methuselah Foundation, provides grants to anti-aging researchers. Some of the freshest thinking so far has included biomedical remediation, therapeutic organisms purpose-catalyzed in the body and the possibility of removing the overly-prone-to-damage mitochondrial DNA.

Generalized summary of Aging 2008 research findings:

• Applying (non-individual specific) substances from the young to the old appears to work
• With aging, not only does "good stuff" (cells, processes, etc.) decline but "bad stuff" also arises
• The quality of the biological environment facilitates or inhibits activity and repair
• Treatments may be most effective when begun in youth or middle age
• The goal is to extend healthspan not just lifespan

DIY biohacking and the cocktail problem
Every bit as interesting as the scientific talks were the informal discussions of the wide range of interventions, treatments, supplements and other anti-aging remedies in use by conference participants. The cocktail problem is how multiple remedies taken in concert may be impacting each other. Never has there been a market with such demand and so few offerings as for anti-aging remedies.