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The Hallmarks of Aging: Deregulated Nutrient Sensing – Article by Ariah Mackie

The Hallmarks of Aging: Deregulated Nutrient Sensing – Article by Ariah Mackie

Ariah Mackie


Editor’s Note: In this article, Ariah Mackie explains that there are four key proteins involved in nutrient sensing that might be key contributors to aging.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, February 15, 2018

As part of our ongoing series covering the hallmarks of aging, we are taking a look at deregulated nutrient sensing today and how these four pathways regulate metabolism and influence aging.

To understand studies on nutrient sensing in the context of aging, let’s introduce four key protein groups. In this post, we’ll explore the pathways they help control and how they affect aging. These key proteins are IGF-1, mTOR, sirtuins, and AMPK [2]. We call these proteins “nutrient sensing” because nutrient levels influence their activity [2].

IGF-1 and the IIS pathway: The Basics

Insulin-like growth factor (IGF-1) inhibits the secretion of growth hormone (GH) by binding to a special receptor on the surface of a cell [1]. Like insulin, IGF-1 takes part in glucose sensing. Both it and insulin are part of the aptly named “insulin and insulin-like growth factor” (IIS) pathway [2].

Attenuation of the IGF-1/GH pathway (IIS) appears to improve lifespan in several model organisms [1]. For example, PI3K mice, which have a weakened IIS pathway, live longer [2]. Additionally, FOXO, a transcription factor (a protein that affects the production of RNA), lengthens lifespans in worms and fruit flies by attenuating IIS signaling [2]. In other studies, IGF-1 improves healthspan even when it does not lengthen lifespan [2].

There’s also evidence of a harmful impact when IGF-1 activity is high. Higher levels of IGF-1 are associated with increased risk of some types of cancer [1]. This increased cancer risk might be due to IGF’s ability to promote pathways that result in increased cell production [1].

IIS and the Not-So-Basics

IGF-1 expression and the IIS pathway are a bit of a paradox. Since it looks like turning down the IIS pathway promotes longevity, you might expect the IIS pathway to be very active in old organisms. It looks like high IIS ages us, after all. However, that’s not the case. In both accelerated and normal aging models, we see that the IIS pathway decreases [2].

One explanation for this weirdness is that it’s a last-ditch measure of the organism to increase its own lifespan. Yet, this short-term decrease in IIS activity can be harmful. In fact, it is so harmful that IGF-1 supplementation is beneficial [2]. What this seems to point to is a dichotomy concerning the expression of IIS. Overall, it looks like turning down the IIS pathway is good over the long term for longevity. This might be because it causes the reduction of metabolism and cell growth, which lessens wear and tear [2]. However, the body’s attempt to do the same in later life goes too far and too late to be truly beneficial.

How IGF-1 affects human lifespan is still fuzzy as well [1]. On one hand, there is an indication of a longevity effect with reduced IGF-1 activity in those with Laron syndrome (who don’t have functional growth hormone receptors), female nonagenarians, and extremely long-lived people [1]. Yet, the epidemiological data is not clear enough to be conclusive on IGF-1’s effects on humans [1]. This is partially due to the difficulty of structuring epidemiological studies on IGF-1, as many external factors, such as nutrition, can confound results [1].

mTOR

Mechanistic target of rapamycin (mTOR) is composed of the mTORC1 and mTORC2 protein complexes. It senses amino acids and is associated with a nutrient abundance [2]. It is a kinase, which means it adds phosphates to molecules [2]. mTOR is a champion regulator of anabolic metabolism [2], the process of building new proteins and tissues. In this way, how it functions is similar to the IIS pathway [2]. At any given moment, the metabolism is either breaking down old parts (catabolism) or building new ones (anabolism). Both mTOR and the IIS are part of the anabolic side of metabolism.

Lower activity of mTOR lengthens lifespan in model organisms, such as mice, yeast, worms, and flies [2]. Along those lines, mTOR activity increases in the hypothalami of aged mice, which promotes late-life obesity. With rapamycin, an inhibitor of mTOR, these effects are ameliorated [2]. As is the case with, IIS, lowered expression of mTOR is not always beneficial. Low expression of mTOR can harm healing and insulin sensitivity and can cause cataracts and testicular generation in mouse models [2].

Sirtuins

Sirtuins are a family of proteins that act as NAD(+) dependent histone deacetylases [2]. To explain what that means, let’s start with histones. Histones are the proteins that DNA wraps around. They serve as a way to compact the DNA (which is very long) in the nucleus, especially during cell division. Histones also help control the expression of genes by spatially making some genes more or less available for proteins like RNA polymerase to attach. On histones, there are lysines, a type of amino acid. It is on these lysines that histone deacetylases remove acetyl groups, which are small molecules. If that sounds too confusing, remember this: adding or removing acetyl groups helps control the expression of genes. In such a manner, sirtuins help control gene expression.

Sirtuins detect when energy levels are low by sensing the coinciding increase of NAD+ [2]. They also help control catabolic metabolism [2]. Upregulating some sirtuins produces anti-aging or health-promoting effects [2]. However, some sirtuins have only weak effects in some species, which makes summarizing their effects difficult. For example, in worms, higher expression of SIR2 yields only slight gains in longevity [2]. Overexpression of SIR2’s most similar counterpart in mice, SIRT1, appears to improve health during aging but not lifespan [2].

Another mouse sirtuin, SIRT6, seems to promote longevity more robustly [2]. Mice deficient in it experience accelerated aging. Conversely, turning it up results in increased longevity [2]. There is also SIRT3, which has been shown to help the regeneration ability of old hematopoietic (blood and immune cell producing) cells when overexpressed [2].

AMPK

AMP-activated kinase (AMPK) senses AMP (adenosine monophosphate) and ADP (adenosine diphosphate). These long-named molecules are present in higher quantities when nutrients are scarce [2].Therefore, it is easiest to remember AMPK as a sensor of fasted or calorie-restricted states and catabolism [2]. Molecularly, AMPK acts by adding phosphates to serine and threonine [3]. By doing so, AMPK helps regulate metabolism [2].

Like sirtuins, higher activity of AMPK has longevity-promoting effects [2]. To illustrate, metformin, a diabetes drug that appears to have a life-extension effect, activates AMPK in mice and worms [2]. Calorie restriction, which is known to increase lifespan in at least short-lived animals, can also increase the activity of AMPK [3]. Conversely, less AMPK sensitivity due to cellular stress results in oxidative stress, reduced autophagy, metabolic syndrome, more fat disposition, and inflammation [3].

Conclusion

In summary, there are four key proteins involved in nutrient sensing that might be key contributors to aging. Turning down the pathways of the first two, IGF-1 and mTOR, promote longevity. Both of these are involved in anabolic metabolism (building tissues) and increase in states of nutrient abundance[2]. Conversely, turning up the activity of the last two, sirtuins and AMPK, helps longevity. They work to promote catabolic metabolism (breaking down tissues) and increase with nutrient scarcity [2].

References

[1] Milman, S., Huffman, D. M., & Barzilai, N. (2016). The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research. Cell Metabolism, 23(6), 980-989. doi:10.1016/j.cmet.2016.05.014

[2] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[3] Salminen, A., & Kaarniranta, K. (2012). AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Research Reviews, 11(2), 230-241. doi:10.1016/j.arr.2011.12.005

About Ariah Mackie

Ariah received a Bachelor’s Degree in Biomolecular Engineering from the University of California in Santa Cruz in 2016. Her career interests are in regenerative medicine for aging, teaching, computational biology, genomics, and bioinformatics.

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

Hallmarks of Aging: Epigenetic Alterations – Article by Steve Hill

Hallmarks of Aging: Epigenetic Alterations – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Mr. Steve Hill discusses one of the hallmarks of aging – in this case, Epigenetic Alterations. It is part of a paper published in 2013. It divides aging into a number of distinct categories (“hallmarks”) of damage to explain how the aging process works and how it causes age-related diseases [1]. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                        ~ Kenneth Alum, Director of Publication, U.S. Transhumanist Party, October 18, 2017

What are epigenetic alterations?

The DNA in every one of our cells is identical, with only small variations, so why do our various organs and tissues look so different, and how do cells know what to become?

DNA is modified by the addition of epigenetic information that changes the pattern of gene expression in a cell, suppressing or enhancing the expression of certain genes in a cell as the situation demands. This is how a cell in the liver knows that it needs to develop into a liver cell; the epigenetic instructions make sure that it is given the right orders to become the correct cell type.

At a basic level, these epigenetic instructions make sure that the genes needed to develop into a liver cell are turned on, while the instructions specific to other types of cells are turned off. Imagine if a heart cell was given the wrong instructions and became a bone cell!

How epigenetic alterations accumulate

The aging process can cause alterations to our epigenome, which can lead to alterations in gene expression that can potentially change and ultimately compromise cell function. As an example, epigenetic alterations of the immune system can harm activation and suppress immune cells, thus causing our immune system to fail and leaving us vulnerable to pathogens.

Inflammation is implicated in epigenetic alterations, and studies show that caloric restriction slows the rate of these epigenetic changes [2]. Metabolism and epigenetic alterations are closely linked with inflammation, facilitating a feedback loop leading to ever-worsening epigenetic alterations. Alterations to gene expression patterns are an important driver of the aging process. These alterations involve changes to DNA methylation patterns, histone modification, transcriptional alterations (variance in gene expression) and remodeling of chromatin (a DNA support structure that assists or impedes its transcription).

In the cell, gene expression is activated by hypomethylation (a loss of methylation) or silenced by hypermethylation (an increase of methylation) at a gene location. The aging process causes changes that reduce or increase methylation at different gene locations throughout the body. For example, some tumour suppressor genes become hypermethylated during aging, meaning that they cease functioning, which increases the risk of cancer [3]. Post-translational modifications of histones regulate gene expression by organizing the genome into active euchromatin regions, where DNA is accessible for transcription, or inactive heterochromatin regions, where DNA is compacted and less accessible for transcription. The aging process causes changes to these regions, which changes gene expression.

The aging process also causes an increase in transcriptional noise, which is the primary cause of variance in the gene expression happening between cells [4]. Researchers compared young and old tissues from several species and identified age-related transcriptional changes in the genes encoding key components of inflammatory, mitochondrial, and lysosomal degradation pathways [5].

 Finally, chromatin remodeling alters chromatin from a condensed state to a transcriptionally accessible state, allowing transcription factors and other DNA binding proteins to access DNA and control gene expression.

Conclusion

If we can find ways to reset age-related epigenetic alterations, we can potentially improve cell function, thus improving tissue and organ health.

One potential approach is the use of reprogramming factors, which reset cells to a developmental state, thus reverting epigenetic changes. We have been doing this for over a decade to create induced pluripotent stem cells, and recent work has seen a therapy based on that technique applied to living animals to reset their epigenetic alterations [6]. This reversed a number of age-related changes, and work is now proceeding with the goal of translating this to humans.

Epigenetic alterations might be considered like a program in a computer, but in this case, it is the cell, not a computer, being given instructions. Ultimately, damage causes changes that contribute to the cell moving from an efficient “program” of youth to a dysfunctional one of old age. If we can reset that program, we can potentially address this hallmark of aging, and a number of researchers are working on that right now.

 

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Maegawa, S., Lu, Y., Tahara, T., Lee, J. T., Madzo, J., Liang, S., … & Issa, J. P. J. (2017). Caloric restriction delays age-related methylation drift. Nature Communications, 8.
[3] Maegawa, S., Hinkal, G., Kim, H. S., Shen, L., Zhang, L., Zhang, J., … & Issa, J. P. J. (2010). Widespread and tissue specific age-related DNA methylation changes in mice. Genome research, 20(3), 332-340.

[4] Bahar, R., Hartmann, C. H., Rodriguez, K. A., Denny, A. D., Busuttil, R. A., Dollé, M. E., … & Vijg, J. (2006). Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature, 441(7096), 1011-1014.

[5] De Magalhães, J. P., Curado, J., & Church, G. M. (2009). Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics, 25(7), 875-881.

[6] Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Araoka, T. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell, 167(7), 1719-1733.

 

About Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies, Steve has provided the community with multiple educational articles, interviews, and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity Reporter, Psychology Today, and Singularity Weblog. He is a co-author of the book Aging Prevention for All – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

Hallmarks of Aging: Genomic Instability – Article by Steve Hill

Hallmarks of Aging: Genomic Instability – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Mr. Steve Hill discusses one of the hallmarks of aging – in this case, Genomic Instability. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

~ Kenneth Alum, Director of Publication, U.S. Transhumanist Party, October 17, 2017

What is genomic instability?

The cells of your body produce a constant flow of proteins and other materials; these are built according to the blueprints contained in our DNA and are vital to cell function and survival. A large amount of information contained in the DNA is ignored during this process, and this is thought to be junk DNA, remnants of our evolutionary past that are no longer used.

However, if a part of the DNA important to cell function mutates or is damaged, the cell can experience a loss of proteostasis, in which the cell produces misfolded proteins. These misfolded proteins can be very harmful, such as when neurons in the brain produce masses of the toxic amyloid beta protein, as seen in Alzheimer’s disease.

Now, the odd dysfunctional cell is not really a huge problem; however, as we get older, an increasing number of cells succumb to this damage and begin to accumulate in tissue over time. Eventually, the number of these damaged cells reaches a point where tissue or organ function is compromised. Normally, the body removes these problem cells via a self-destruct sequence known as apoptosis, a sort of kill switch that senses the damage and destroys the cell in conjunction with the immune system.

Unfortunately, some cells evade apoptosis, taking up space in the tissue and pumping out inflammatory signals that damage the local tissue. These cells are known as senescent cells, and we will be covering them in a later Hallmarks article.

Another possible outcome of damaged DNA is cells that mutate and do not become senescent cells or destroy themselves via apoptosis. These cells continue to replicate, becoming more mutated each time they divide, and if a mutation damages the systems that regulate cell division or switches off the safety mechanisms against tumor formation, this can lead to cancer. The unchecked and rampant cell growth of cancer is probably the most well-known result of genomic instability.

How DNA damage accumulates

There are many ways for DNA to become damaged. UV rays, radiation, chemicals, and tobacco are all examples of environmental stressors that can damage the genome. Even chemotherapy agents designed to kill cancer can also potentially cause DNA damage and senescent cells, leading to later relapse [2].

Finally, even if we avoided all the external threats to our DNA, the body still damages itself. Reactive oxygen and nitrogen species produced during the operation of normal metabolism can damage both DNA and mitochondrial DNA.

Thankfully, we have evolved a robust network of repair systems and mechanisms that can repair most of this damage. We have enzymes that can detect and repair broken strands of DNA or reverse alterations made to base pairs. This repair process is not perfect, and sometimes the DNA is not repaired. This can lead to the cell replication machinery misreading the information contained in the DNA, causing a mutation.

As mutations are passed to daughter cells, the cell tries to prevent this from happening by checking DNA integrity before and after replication. Unfortunately, some cells do manage to slip through the net.

The consequences of DNA damage

A large number of age-related diseases are linked to damaged DNA or faulty DNA repair systems. Alzheimer’s, Parkinson’s, Lou Gehrig’s disease (ALS), and cancer are all the result of genomic instability.

Another example are the progeric diseases. Progerias are congenital disorders that result in rapid aging-like symptoms and a dramatically shortened lifespan, with Hutchinson-Gilford progeria syndrome (HGPS) probably being the most well known. The disease is caused by a defect in Lamin A, a major component of a protein scaffold on the inner edge of the nucleus called the nuclear lamina. The lamina helps organize nuclear processes, such as RNA and DNA synthesis, and lamins are responsible for supporting key proteins in the DNA repair process.

This defect leads to HGPS sufferers only living until their early 20s and developing atherosclerosis, stiff joints, hair loss and wrinkles, and other accelerated aging-like characteristics.

Conclusion

Despite the various repair systems we have evolved, our body is constantly being assaulted from exposure to environmental stressors and even damaged through its own metabolic processes. Coupled with this, our repair systems also decline in effectiveness over time, meaning that DNA damage and mutations are inevitable.

There is some evidence to suggest that caloric restriction may help combat this, but as of now, no drugs or therapies are available yet that can prevent or repair DNA damage. The good news is human trials for DNA repair are launching this year at Harvard, and Dr. David Sinclair and other researchers are also working on their own solutions.

For the time being, the best we can do is to avoid risks, such as excessive sun exposure, industrial chemicals, smoking, and, of course, staying away from radioactive waste; there are no comic-book superpowers from these mutations!

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Demaria, M., O’Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., … & Alston, S. (2017). Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer discovery, 7(2), 165-176.

About Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies, Steve has provided the community with multiple educational articles, interviews, and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity Reporter, Psychology Today, and Singularity Weblog. He is a co-author of the book Aging Prevention for All – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.