We talk about aging a lot, but what does it really mean?
By Steve Hill and Elena Milova
It is strange really, we hear people talking about aging all the time, about the aches and pains, grey hairs and wrinkles and yet few of us really understand the complex biology that is at work driving these processes. So let us explore what we know about aging so far thanks to science, but before we do it is important to define aging in order to better understand it.
According to modern science, aging is the accumulation of error that the body cannot completely eliminate, due to the imperfections of its protection and repair system. As a result, bodily functions start to deteriorate, leading ultimately to the development of age-related diseases, such as cancer, stroke, type 2 diabetes, heart diseases, Alzheimer’s disease, osteoarthritis, osteoporosis and others.
Aging comprises of a number of distinct and interconnected processes which we will explore briefly in the following sections. Once you begin to understand the processes of aging it becomes possible to understand the ways we might intervene against them in order to treat and prevent age-related diseases, hence enabling people to live healthier lives for longer.
Genomic instability is considered one of the main causes of aging. Somatic cells are constantly exposed to a range of sources of DNA damage, from reactive oxygen species, UV radiation to environmental mutagens. DNA serves as a production plant for the proteins (small building blocks of the cell). When DNA is damaged, some proteins can stop being produced or can have the wrong shape, which, in turn, compromises the function of the cell. When there are many cells with this kind of damage in the organ, some important body functions can start to deteriorate.
To cope with this constant assault the body has developed a complex network of repair and maintenance system that act to remove damage and repair the DNA. These same systems include mechanisms for maintaining telomere length and function for a stable gene expression profile and thus a stable genome. This system also includes mechanisms to maintain the integrity of mitochondrial DNA (mtDNA). It is important to note that this genomic damage is largely stochastic in nature.
Factors contributing to loss of genomic stability are varied and the kinds of effects they have are broad such as, somatic mutations, chromosomal aneuploidies, Mutations and deletions in aged mtDNA, Defects in the nuclear lamina. All these things are part of loss of genomic stability via damage to the DNA and mtDNA. The most well-known consequence of this process is cancer.
DNA damage during aging appears to be a stochastic process. However, chromosomal regions such as the telomeres have a somewhat more predictable pattern of deterioration. Telomere loss is technically a subset of genomic instability but warrants its own category as a form of aging damage due to this more predictable nature.
Telomeres are a protective cap at the end of a chromosome. Each time a cell divides, telomeres get increasingly shorter and once they become critically short the cell ceases to divide and enters replicative senescence, better known as the Hayflick limit. Importantly, as telomeres shorten they influence the gene expression profile (the production of proteins) of a cell changing it from a functionally young one to an old one.
Fig 1. Replicative senescence aka the Hayflick limit.
Now nature has a solution to this problem, the expression of Telomerase which is an enzyme able to extend telomeres. This specialized DNA polymerase solves this end replication problem and allows complete replication to occur during cell division, keeping the cell young. However, most human somatic cells do not express telomerase which leads to progressive attrition of the protective telomere caps and ultimately cell aging and death. Even in stem cells activity of telomerase appears to decline with age likely due to the other aging damages influencing expression and signaling.
In humans telomerase deficiency leads to various conditions including pulmonary fibrosis (the lungs become scarred and breathing becomes increasingly difficult), dyskeratosis congenita (a rare genetic form of bone marrow failure, the inability of the marrow to produce sufficient blood cells) and aplastic anemia (deficiency of all types of blood cell caused by failure of bone marrow development) due to the loss of regenerative capacity in various tissues, and telomerase therapy can help reverse disease. Short telomeres are also implicated in heart disease, and diabetes mellitus, and as such present a potential therapeutic target.
Changes to gene expression patterns (deactivation of useful genes and activation of potentially harmful ones) are a key influence in aging. These changes involve alterations to DNA methylation patterns (deactivation or activation of different genes), histone modification, transcriptional alterations (variance in gene expression) and remodelling of chromatin (DNA support and package structure, assisting or impeding its transcription). Generally speaking, these changes (known as epimutations) lead to detrimental changes in gene expression patterns.
Gene expression is controlled in the cell by hypomethylation (loss of methylation) or blocked by hypermethylation (increase of methylation) at a gene location. The aging process makes global changes that reduce or increase methylation at different gene locations. Some tumour suppressor genes become hypermethylated during aging for example, this means they do not function increasing the risk of cancer.
Post-translational modifications to histones regulate gene expression by organizing the genome into active regions of euchromatin, where DNA is accessible for transcription, or inactive heterochromatin regions, where DNA is more compact and less accessible for transcription. Aging causes changes to these regions, thus influencing gene expression.
The aging process causes an increase in transcriptional noise, which is a primary cause of variance in gene expression occurring between cells. In microarray comparisons of young and old tissues from several species the scientists have identified age-related transcriptional changes in genes encoding key components of inflammatory, mitochondrial and lysosomal degradation pathways .
Chromatin remodeling are changes to 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..
Fig 2. Some of the processes of epigenetic changes and transcription.
Epigenetic alterations are a complex and not fully understood process. They can be considered almost like a program in a computer, but in this case it is the cell, not the computer, being given instructions. Ultimately these changes contribute to the cell moving from an efficient “program” of youth to a dysfunctional one of the old age. However the process appears to be plastic and is not the one way process people once assumed. Indeed recent research shows that Epigenetic alterations can be made to reverse this process of aging to restore youthful function and increase lifespan.
Loss of proteostasis
Proteostasis is the process by which cells control the abundance and folding of the proteins – building blocks of each cell. Proteostasis consists of a complex network of systems that integrates the regulation of gene expression, signaling pathways, molecular chaperones and protein degradation systems.
Aging is linked to the impairment of proteostasis and the various quality control systems it incorporates. Even during regular operation misfolding of proteins can occur and they are immediately broken down and recycled. However with aging and the decline of proteostasis misfolded proteins increase and lead to aggregation. One of the best known consequences of this is the accumulation of amyloids which results in the development of diseases such as Alzheimer’s and Parkinson’s.
Recently research approaches to improve the function of macrophages have shown potential in removing the accumulated amyloids giving hope for treating diseases like Alzheimer’s, and other work on misfolded proteins is showing similar promise.
Deregulated nutrient sensing
The scientific evidence to date suggests that anabolic signaling (internal alarm about the abundance of nutrients) appears to accelerate aging, and that decreased nutrient signaling is shown to extend lifespan. We see from experiments, that adjusting signalling using substances like Rapamycin to mimic limited nutrient availability can increase lifespan in mice. This aging category comprises four main pathways: the IIS Signaling pathway, mTOR, AMPK, and Sirtuins
The Insulin and Insulin-like growth factor 1 (IGF-1) Signaling pathway (IIS pathway) informs the cells in the body of the presence of glucose. It is composed of growth hormone (GH) created in the pituitary gland in mammals, and .IGF-1 which is produced in response to GH by many types of cells, forming the somatotrophic axis. IGF-1 shares the same signaling pathway as insulin. The IIS pathway is a conserved aging-controlled pathway from our evolutionary past. This pathway has various targets including FOXO and mTOR, both involved with aging. When there is a reduction of the functions of the GH, IGF-1 receptor, insulin receptor or its downstream intracellular targets, we see an increase in lifespan.
Consistent with deregulated nutrient sensing, we see that dietary restriction increases lifespan in various species. There is also increasing evidence for the healthspan benefits of dietary restriction in humans. So it seems, reducing the IIS pathway can encourage longevity.
However contrary to this, as we age levels of GH and IGF-1 also decline, which is seemingly a paradox. So why the decreased GH and IGF-1 levels via interventions such as dietary restriction and Rapamycin are beneficial, and yet their falling levels with aging are not? Well the answer is, they are both beneficial.
Falling levels of IIS with age can be explained as the body putting the brakes on and slowing down aging by reducing cell growth and slowing metabolism in an attempt to survive. If the body did not adjust these levels as we were growing older, then we would almost likely age even more rapidly than we currently do. This would suggest that the idea we are “programmed to die” is incorrect because here is proof that the body is trying to live longer by doing this.
The nutrient sensing mechanistic target of rapamycin (mTOR) pathway is another regulator of aging. mTOR signaling is complex and affects several important cellular functions. Two such functions, which influence aging, are protein synthesis (creation of proteins) and autophagy (misfolded protein digestion). The mTOR pathway is closely connected to the IIS pathway mentioned above, and the two work together signaling nutrient abundance.
The last two pathways, AMP-activated protein kinase (AMPK) and sirtuins, are catabolic signaling systems (they signal nutrient scarcity) and act in the opposite way to the IIS and mTOR pathways. Increasing levels of these two pathways favours health and longevity (the opposite to IIS and mTOR which reduces lifespan when levels are increased). They work together in a feedback loop to provide a unified response to low energy states. Together AMPK and sirtuins sense low energy states, by detecting high AMP levels and high NAD+ levels respectively.
AMPK activation has a number of effects on metabolism and autophagy. It has been shown to influence lifespan in mice which were given Metformin. AMPK even inhibits the mTOR signaling pathway, increasing autophagy.
Sirtuins are perhaps best known for their longevity promoting effects in the experiments with dietary restriction in various animal species. Sirtuins adjust cellular metabolism due to nutrient availability and also regulate many metabolic functions, including DNA repair, genome stability, inflammatory response, apoptosis, cell cycle, and mitochondrial functions.
Mitochondria are the “power plants” of the cells: they convert the energy-rich nutrients in our food into ATP, a form of energy that directly powers the biochemical reactions in the cell.
Unlike any other part of the cell, mitochondria have their own DNA (mtDNA), separate from the DNA in the cell’s nucleus, where all the rest of our genes are kept. As part of their normal operation the mitochondria generate waste products during the process of “burning” food energy as fuel and as a result they spew out free radicals, which can damage cellular structures. Due to its proximity to the centre of production, the mtDNA is especially vulnerable to damage from these free radicals. A free radical strike to the mtDNA can cause deletions in its genetic code, destroying the mitochondria’s ability to make proteins that are critical components of their energy-generating system.
Without the ability to produce cellular energy the normal way, these damaged mutant mitochondria enter into an abnormal metabolic state to survive. This state produces little energy, and generates large amounts of waste that the cell cannot metabolize. Strangely, the cell favours keeping these defective, mutant mitochondria, while recycling normal ones. This means that if just one mitochondrion suffers a mutation, its progeny will take over the entire cell.
Whilst this only happens to a few cells in our body, these cells do a large amount of damage to the body as a whole. Damage occurs due to the waste from the mutant mitochondria entering the system, causing oxidative stress levels to rise and effectively poisoning the rest of the system. This activates the NF-κB pathway and contributes to “inflammaging.” (see Altered intercellular communication) leading to a host of problems including increased apoptosis (cell death) and systemic inflammation.
Thankfully science is making steady progress towards rejuvenating the mitochondria to address the damage described above. The SENS Research Foundation published a paper in 2016 showing the plausibility of mitochondrial repair which was the result of the MitoSENS project. In September 2016 Dr.Matthew O’Connor from SENS Research gave a presentation about the project results and the future possibilities at a Google Tech Talk.
As the body ages, increasing amounts of cells enter a state of senescence. Senescent cells do not divide or support the tissue they are a part of, but instead emit a range of potentially harmful signals known collectively as the senescent associated secretory phenotype (SASP).
Senescent cells normally destroy themselves via a programmed process called Apoptosis and they are removed by the immune system, however the immune system weakens with age, increasing numbers of these senescent cells escape this process and build up. By the time people reach old age significant numbers of these senescent cells have accumulated in the body and cause havoc, driving the aging process further and increasing the risk of diseases.
An additional effect of senescent cells is their potential to influence nearby cells too. The production of SASP encourages other nearby cells to also enter senescent state, increasing the scale of the problem further. This ability of senescent cells to infect neighboring cells is sometimes called the ‘bystander effect’ and is also part of Altered intercellular communication, another process of aging, discussed later in this section.
Senescent cell accumulation causes many problems: they degrade tissue function, increase levels of chronic inflammation that drives the aging process, and can even eventually raise the risk of cancer, heart disease, and shorten lifespan.
The removal of these cells is therefore a potential avenue of therapy. Indeed, senescent cells eradication has been the focus of numerous recent research efforts with some spectacular results.
Senescent cell accumulation is a problem as you age but fortunately science is getting close to a possible solution which will shortly be moving into human clinical trials with companies like Unity Biotechnology. You can read more about the promising progress with therapies that remove senescent cells in our technology section here.
Stem cell exhaustion
Every day, our cells are damaged. Some of these damaged cells are successfully repaired and keep serving the body. Others are either completely destroyed via apoptosis, or become dysfunctional and enter a ‘senescent’ state where they can no longer divide (see Cellular senescence). Some of these lost cells are replaced from reserves of tissue-specific stem cells, but the aging process makes these stem cell pools less effective at repairs over time, and eventually those reserves run out.
The Immune system in particular is compromised by depletion of its stem cells. Hematopoiesis (creation of blood cells) declines with age, resulting in a diminished production of adaptive immune cells, a process termed immunosenescence. The thymus, a key part of the immune system that produces immune cells, constantly shrinks, leaving you vulnerable to infectious disease and cancer as fewer new cells are created.
Over the passage of time, long-lived tissues, such as those in the brain, heart, and skeletal muscles, begin to progressively lose cells, and their function becomes increasingly compromised. Muscles weaken, and don’t respond to exercise. The brain loses neurons, leading to cognitive decline and dementia, as well as to loss of control over fine muscle movements and Parkinson’s disease. Ultimately the loss of reserves of replacement cells leads to the failure of tissue repair and is a significant driver of aging. Thus, cell therapies aimed at refilling stem cell pools in future might become an important part of maintaining health in old age.
Altered intercellular communication
Aging causes changes to communication outside of the cell, which ultimately affects the function of all cells and tissues. Cellular communication has endocrine (hormones from pineal gland, pituitary gland, pancreas, ovaries, testes, thyroid gland, parathyroid gland, and adrenal glands), neuroendocrine (hormones from nerve and gland cells) or neuronal origins. Neurohormonal signaling becomes increasingly deregulated with age as inflammatory reactions increase.
One of the best known age-related changes in intercellular communication is the chronic inflammation (often called ‘inflammaging’), which implies an increasingly rising background level of inflammation as we age. Inflammaging results from various sources, such as the accumulation of pro-inflammatory tissue damage, the failure of the immune system to effectively remove pathogens and precancerous cells, accumulation of senescent cells (see cellular senescence) that result in pro-inflammatory signals, defective autophagy responses, and finally the increased activity of the proinflammatory NF-κB pathway, which has been shown to increase inflammation in senescent cells and microbial infectious burden
In addition to inflammatory signals, the so called bystander effect, in which senescent cells induce senescence in neighboring cells through the toxic signals they give off, is also a part of altered intercellular communication (see cellular senescence). Indeed, like the various aging processes, senescent cells and Altered intercellular communication are closely linked. Studies suggest that many age-related diseases are caused or worsened by systemic inflammation, including neurodegeneration, and atherosclerosis.
Long-lived protein modification
A suspected cause of degenerative aging is the accumulation of sugary metabolic wastes known as advanced glycation end-products (AGEs). These are wastes that are in some cases hard for our metabolism to break down fast enough or even at all. Some types, such as glucosepane, can form cross-links, gumming together important proteins like those making up the supporting extracellular matrix scaffold. The properties of elastic tissues (skin and blood vessel walls) derive from the particular structure of the extracellular matrix, and cross-links degrade that structure, preventing it from functioning correctly. AGEs presence contributes to blood vessel stiffening with age. and is implicated in hypertension and diabetes.
These are the main processes of aging known to date. Indeed we can see that aging contributes to health deterioration via a number of distinct but linked biological processes. Thus, aging is the main cause of the development of severe age-related diseases, such as cancer, stroke, type 2 diabetes, Alzheimer’s, Parkinson’s, osteoarthritis and many others.
In animal studies it was found that by addressing even one of these processes at a time it is possible to postpone, slow down or even reverse several age-related diseases, enabling the animals to remain healthier for longer. This data shows that the aging processes represent a viable therapeutic target. But in order to achieve the best outcomes, innovative therapies aimed at modulating aging processes and preventing the onset of diseases have to be applied in middle age or even earlier in life.
The process of translating these findings into therapies for humans is on the way. Many existing drugs were found to influence the aging processes in humans, many new interventions are now at the stage of clinical trials, and in the next decades we will see them implemented into clinical practice. That is why it is so important to start informing the wider public about the potential of these preventive therapies today and to support projects that progress fundamental gerontology and increase scientific understanding.