Hallmarks of Aging PDF

[The hallmarks of ageing.] López-Otín C, et al. Cell. 2013 Jun 6;153(6):1194-217. Concludes there are currently 9 identifiable "hallmarks of ageing" that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. Each hallmark should [ideally] fulfill...

[The hallmarks of ageing.] López-Otín C, et al. Cell. 2013 Jun 6;153(6):1194-217. Concludes there are currently 9 identifiable "hallmarks of ageing" that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. Each hallmark should [ideally] fulfill the following criteria: \(1) it should manifest during normal aging; \(2) its experimental aggravation should accelerate aging; and \(3) its experimental amelioration should retard normal aging and increase healthy lifespan. The last criterion = most difficult to achieve. For this reason, not all of the hallmarks are fully supported yet by interventions that succeed in ameliorating aging. The time-dependent accumulation of cellular damage = general cause of aging. Based on this framework, several critical questions have arisen in the field of aging regarding the physiological sources of aging-causing damage, the compensatory responses that try to reestablish homeostasis, the interconnection between the different types of damage and compensatory responses, and the possibilities to intervene exogenously to delay aging. **[1. Genomic instability]**: A common denominator of aging is the accumulation of genetic damage throughout life. Many premature aging diseases are the consequence of [increased DNA damage accumulation].Genomic instability can be caused in two ways: 1. i. ii. Organisms have evolved a complex network of **DNA repair mechanisms** that are collectively capable of dealing with most of the direct damages inflicted including systems dedicated to maintain telomere length/functionality and the integrity of mitochondrial DNA: i. The mitochondrial DNA (mtDNA) is a major research target for aging-associated mutations because of: - - - **But!** Research has shown that: - - - 2. iii. iv. In normal aging: - - Damage to the nuclear lamina causes the following stress pathways to become active (causing premature aging): - - - The cause → effect relationship of the laminopathies on aging has been demonstrated by: - - - **[2. Telomere attrition]**: Telomeres are particularly susceptible to age-related deterioration because: - - Telomerase deficiency in humans → premature development of diseases that involve the loss of regenerative capacity of tissue Shelterin deficiency in humans → severe telomere uncapping, rapid decline of regenerative capacity of tissue and accelerated aging.(**shelterin is necessary but also increases the impact of damage to telomeres)** [Experimentally increasing telomere length] (in mice) leads to longer lifespans. Genetically activating telomerase can revert and delay aging (especially in telomerase-deficient mice) without increasing the incidence of cancer. **[3. Epigenetic alterations:]** There are a number of different epigenetic alterations that can all be viewed as hallmarks of aging: 3. a. b. 4. c. d. e. 5. f. g. h. 6. i. j. k. Unlike DNA mutations: reversion of epigenetic alterations is theoretically possible → **novel anti-ageing treatment possibilities!** Some research has already been done in mice to experimentally alter some of these epigenetic factors with successful results. Especially SIRT6 (a stress-responsive enzyme produced by the SIRT6 gene) is relevant because **loss** of this enzyme = **reduced** longevity and **gain** of this enzyme = **increased** longevity in mice. **[4. Loss of proteostasis:]** The loss of proteostasis can be described as the combination of: - - Loss of proteostasis plays an important role in different age-related diseases, most notable of which is Alzheimer's disease. Proteins are large, complex molecules that regulate almost everything in the human body, either directly or indirectly. They do the majority of the work in cells and are critical for the function, regulation and structure of tissues and organs. Proteins are made up of hundreds or even thousands of smaller parts called **amino acids**, which are linked together in long chains. There are a total of 20 amino acids that can be combined in many different ways to create a protein. The order in which the amino acids are connected determines the unique structure of a protein and how it functions. Proteins can be categorized according to their function: - - - - - **Proteostasis** = 'protein' (a molecule that a cell uses as a machine or scaffolding) and 'stasis' (meaning to keep the same). The body tries to keep the production of proteins stable and without any defects; this ideal state is known as proteostasis: - - Because these errors in the protein production system [accumulate over time], the loss of proteostasis is considered to be a primary reason why we age and why we develop certain age-related diseases: - - Ideally: unwanted/misfolded proteins are broken down by the cellular machinery. **But**: clumps inherently protect the interior proteins from being broken down and recycled! A recent example of a gene mutation that was found to lead to fragile protein production and an elevated risk of Alzheimer's is the **APOE4 mutation**. **[5. Deregulated nutrient sensing:]** The four "**pathways of nutrient-sensing**" regulate metabolism and influence aging. There are four key protein groups associated with these pathways. Their activity is influenced by nutrient levels (hence nutrient-sensing): **1. IGF-1** = **insulin-like growth factor 1**. This protein group is made mostly by the liver in response to rising levels of **growth hormone** (GH). Then when the IGF-1 level rises, it creates a negative feedback loop on the secretion of **growth hormone** (GH) which lowers GH again. Just like insulin, IGF-1 takes part in **glucose sensing**. Both IGF-1 and insulin are therefore part of the "**insulin and insulin-like growth factor" (IIS) pathway**. a. i. ii. b. c. There's a **paradox** with the IIS pathway! Because turning its activity **down** results in longer life, we would expect the IIS pathway to be very **active** in old individuals. **But**: this is **not** the case! The pathway's activity **decreases** with age, which could be a last-ditch measure of the organism to increase its own lifespan. **2. mTOR** = **mechanistic target of rapamycin**. This group is composed of the **mTORC1** and **mTORC2** protein complexes (both **kinases**, meaning they add phosphates to molecules). mTOR **senses amino acids** and is a regulator of **anabolic metabolism** (the process of building new proteins and tissues). 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. a. b. c. There's a similar **paradox** here: lower expression of mTOR is **not always beneficial!** Low mTOR activity can make healing difficult, cause cataracts (staar in het Nederlands) and testicles to develop (also in female mice) as well as lower insulin sensitivity (effectively giving them diabetes). **3. Sirtuins** = a family of proteins that act as **NAD(+)-dependent histone deacetylases**. Let's deconstruct that: - - - Sirtuins fall into the category of "nutrient-sensing" because they detect [low energy levels] through the [concurrent increase of NAD+ levels]. Upregulating some sirtuins → anti-aging or health-promoting effects. **But** since not all sirtuins show an effect **and** some only show a weak effect in some species: difficult to summarize sirtuin effects overall. Some specific examples: - - - - **4. AMPK** = **AMP-activated kinase**. This group of proteins sense AMP (**adenosine monophosphate**) and ADP (**adenosine diphosphate**). When nutrients are [scarce], these molecules are present in higher quantities. Easiest to remember: AMPK = a sensor of fasted or calorie-restricted states and catabolism (breaking down old parts). AMPK adds phosphates to serine and threonine (amino acids), which helps regulate metabolism. Like sirtuins, [higher activity] of AMPK → longevity-promoting effects. - - - **[6. Mitochondrial dysfunction:]** As they age, mitochondria: 1. 2. Mitochondria (powerhouses of cells) act like miniature factories: they convert the food we eat into usable energy in the form of a chemical called **adenosine triphosphate** (ATP). ATP fuels a myriad of cellular processes, such as muscle contraction and protein synthesis. For a reference picture of what mitochondria look like see right. Mitochondria did not originate as part of multicellular life; they are stowaways in our cells and have their own unique DNA, which is separate from our own. It is widely thought that they merged with a very early ancestor of all multicellular life to form a symbiotic relationship. Mitochondria become dysfunctional as we age and are host to their own separate (though similar) forms of damage. As we age, our mitochondria change in ways that harm their capabilities as powerhouses and lead them to release **reactive oxygen species** (ROS). ROS cause: - - - - - - Mitochondria from elderly people even look different; they swell up. Their numbers dwindle since they're unable to replace themselves as quickly in their dysfunctional state. ROS can also cause mutations in [mitochondrial DNA.] Some studies suggest that this damage is not imparted directly, but rather that ROS damage the proteins that control the [reproduction of mitochondria] and [introduce additional errors into the copies] by extension. Quality-control mechanisms in the cell detect issues → destroy damaged mitochondria (**mitophagy**). - - As the aging process progresses, NAD+ levels decrease → breakdown in communication between the cell nucleus and the mitochondrial DNA → even more decreased energy production and increased ROS production. A number of methods have been proposed for preventing the harmful effects of mitochondrial dysfunction: 1. 2. **[7. Cellular senescence:]** As you age, increasing numbers of your cells enter into a state known as **senescence**: - - - Normally: worn out/badly damaged cells destroy themselves via a programmed cell death called **apoptosis** → removed by the immune system. **However**, increasing numbers of old and damaged cells escape this process when the immune system gets weaker with age → death-resistant cells accumulate in bodily tissues over time → chronic inflammation and damage to surrounding cells and tissue. Reasons that cells become senescent are: 1. 2. 3. Senescent cells secrete a cocktail of [pro-inflammatory cytokines], [chemokines], and [extracellular matrix proteases], which has been termed the **senescence-associated secretory phenotype** (SASP). Even if the absolute number of senescent cells is small, the SASP significantly contributes to aging and cancer, so targeting these cells as a way to increase longevity seems like a good approach. Studies into this have shown: - - - - - Besides directly removing senescent cells, some researchers have suggested: - - **[8. Stem cell exhaustion:]** While every cell in your body has the same genetic code, different regions of DNA are turned off and on in each one, allowing us to have many unique cell types. Normal cells can't change their epigenetic settings easily, **but** stem cells have greater freedom → some can turn into any cell type in the body. Stem cells perform a wide range of functions. Among others: - - A reduction in stem cell activity = **stem cell exhaustion**. This can have many negative downstream effects such as immunosuppression through reduced production of bacteria-killing and virus-killing white blood cells, muscle loss, frailty, and the weakening of bones. As we age, the activity of our stem cells slowly decreases (we start developing stem cell exhaustion) for multiple reasons: - - - While the pool of stem cells can regenerate itself, it does so with [lower quality and speed] over time → contributes to chronic diseases. In the early days of stem cell research, the most versatile ones were collected from early-stage embryos. Over time, we have found ways to turn adult cells back into stem cells and re-inject them. We call these reprogrammed adult stem cells: **induced pluripotent stem cells (iPSCs;** created by Shinya Yamanaka who was awarded the Nobel Prize). The signaling chemicals that influence ordinary cells into becoming stem cells are now called **Yamanaka factors**. Stem cell research = most mainstream of research topics in the aging field and well-funded: - - - - **[9. Altered intercellular communication:]** The age-associated change in signals [between cells] can lead to some of the diseases of aging, because the signaling environment of chemical messages across the whole body tends to become more inflammatory. This inhibits the immune system and potentially causes muscle wasting, bone loss and other harmful effects in a process known as **inflammaging**. Causes include: - - Inflammation across the body that consistently grows with time → cells increasingly activate a chemical in their nuclei called **nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)**. NF-kB = protein complex that regulates the production of proteins, enzymes, and local signals (cytokines). It is present in almost all cell types and is involved in the cell's responses to stimuli such as stress, cytokines from other cells, free radicals, heavy metals, radiation, oxidized LDL cholesterol, and bacterial or viral antigens. NF-kB is a master regulator of cell activity, and its increase can lead to harmful consequences: - This particular hallmark of aging is closely associated with other hallmarks, mainly cellular senescence, so treating those may have an added benefit in treating this hallmark. Other approaches: - - - [Hallmarks of Aging.] López-Otín C. Cell. 2013 9 identifiable hallmarks in organisms, especially mammals. Criteria: 1\. Occurs in normal aging (non-pathological); 2\. Experimental aggravation accelerates aging; 3\. Experimental amelioration slows aging. \^ Not all hallmarks are fully supported yet by interventions that succeed in ameliorating aging. Framework: cause of aging = time-dependent accumulation of cellular damage. \- Physiological sources of damage? \- Restorative responses that try to reestablish homeostasis? \- Connection between both? \- Possibilities for intervention? **[Hallmark 1: Genomic instability]**: Recurring theme in aging = accumulation of genetic damage throughout life. E.g. many premature aging diseases → increased rate of DNA damage accumulation. **Genomic instability** (frequent mutations) caused in two ways: 1\) Direct damage due to [exogenous] factors (physical/chemical/biological) AND [endogenous] factors (e.g. **DNA replication errors, reactive oxygen species, hydrolysis** etc.) Direct damage = diverse in form (e.g. **point mutations, translocations, telomere shortening**, etc). IF damage affects [essential] genes → dysfunctional cell → damages the whole tissue over time. So: **DNA repair mechanisms** are needed! Deficiencies in those? Accelerated aging. Mitochondrial DNA (**mtDNA**) = a good study subject for the role of direct damage in aging because: - - - **But!** Research has shown that: - - - 2\) Defects in the cell's nucleus called **laminopathies** = mutations in genes coding for nuclear lamins A & B (structural proteins) that make up the **nuclear lamina** (fibrous network inside nucleus). Proteins that directly regulate genomic stability tether themselves to lamin A & B (like scaffolding). Laminopathies? The regulatory proteins can't tether → premature aging. Damage to the nuclear lamina → stress pathways activated (causing premature aging): - - - In normal aging: - - - The effect of laminopathies on aging has been proven by: - - **[Hallmark 2: Telomere attrition]**: Telomeres are particularly susceptible to age-related deterioration because: - - - - Telomerase deficiency in humans → premature development of diseases that involve the loss of regenerative capacity of tissue. Shelterin deficiency in humans → severe telomere uncapping, rapid decline of regenerative capacity of tissue and accelerated aging.(**shelterin is necessary but also increases the impact of damage to telomeres)** [Experimentally increasing telomere length] (in mice) leads to longer lifespans. Genetically activating telomerase → reverts+delays aging (especially in telomerase-deficient mice) w/o increasing cancer incidence. **[3. Epigenetic alterations (4 types):]** 1. a. 2. b. c. 3. d. e. 4. f. g. Reversion of epigenetic alterations is theoretically possible → **anti-ageing treatment possibilities!** Research done in mice: especially SIRT6 (a stress-responsive enzyme produced by the SIRT6 gene). **Loss** of this enzyme = **reduced** longevity. **Increase** of this enzyme = **increased** longevity in mice. **[4. Loss of proteostasis:]** Can be described as the combination of: - - Important role in different diseases, biggest in Alzheimer's disease. Proteins = large, complex molecules; critical for cell function, regulation and structure of tissues. Made up of hundreds or thousands of **amino acids**, linked together in long chains. 20 amino acids total → order in which they're linked determines structure/function of a protein. Categories of proteins: - - - - - **Proteostasis** = 'protein' (used as a machine or scaffolding) and 'stasis' (meaning to keep stable). Aka body tries to keep production of proteins stable and error-free → proteostasis: - - Misfolded proteins accumulate + aggregate (clumps of the same/similar proteins). - - Ideally: unwanted/misfolded proteins are broken down. **But**: clumps inherently protect the interior proteins from being broken down! **APOE4 genetic mutation** leads to fragile protein production and elevated Alzheimer's risk. **[5. Deregulated nutrient sensing:]** Four protein groups associated with the regulation of metabolism and influenced by nutrient levels (hence nutrient-sensing). Metabolism can break down old parts (**catabolism**) or build new ones (**anabolism**) **1. IGF-1** = **insulin-like growth factor 1** (**anabolic**). a. b. **Reducing** insulin and IGF-1 signals → improved lifespan: - - - **Increasing** the signals that IGF-1 can give → increased risk of some types of cancer. - *Hypothesis: reduced IIS signaling → reduces metabolism and cell growth → lessens wear and tear.* **Paradox:** Expectation: IIS pathway is very **active** in old individuals. **Reality:** activity **decreases** with age! Maybe an attempt by the organism to increase its lifespan. **2. mTOR** = **mechanistic target of rapamycin** (**anabolic**). a. b. **Lower** mTOR activity → longer lifespan in mice, yeast, worms and flies. - - **Paradox**: Expectation: lower mTOR = better. **Reality:** low mTOR causes cataracts and lowers insulin sensitivity (causing diabetes). Also causes testicles to develop in female mice and makes wound healing difficult. **3. Sirtuins** = family of proteins that act as **NAD(+)-dependent histone deacetylases**. - - - Sirtuins are "nutrient-sensing" because they detect increased NAD+ levels as a result of low energy. **Increasing** some sirtuin's activity → anti-aging effects. **But** not all sirtuins show an effect! Examples: - - - - **4. AMPK** = **AMP-activated kinase**. a. b. c. AMPK = a sensor of fasted/calorie-restricted state and catabolism. **Increasing** AMPK activity → longevity-promoting effects. - - **Decreasing** AMPK [sensitivity] (body is insensitive to AMPK signals) → oxidative stress, reduced autophagy, more fat deposition, inflammation and metabolic syndrome (high bp, obesity and diabetes)  **[6. Mitochondrial dysfunction:]** As they age, mitochondria: 1. 2. Mitochondria convert food into usable energy → **adenosine triphosphate** (ATP). - Mitochondria have their own unique DNA: **mtDNA.** ROS cause: - - - - - - Elderly mitochondria swell up and are low in numbers (unable to replace themselves quickly). ROS damage proteins that control mitochondrial reproduction → indirect mtDNA mutations/damage. Quality-control mechanisms destroy damaged mitochondria (**mitophagy**). - - With age: NAD+ levels decrease → communication between cell nucleus and mtDNA breaks down → decreased energy production and increased ROS. Proposed interventions for preventing the effects of mitochondrial dysfunction: 1. 2. **[7. Cellular senescence:]** With age increasing numbers of cells enter into **senescence**: - - - Normally: worn out/badly damaged cells undergo **apoptosis** → removed by the immune system. Immune system weakens with age → death-resistant cells accumulate in bodily → chronic damage. Reasons for senescence: 1. 2. 3. **Senescence-associated secretory phenotype** (SASP) = cocktail of [pro-inflammatory cytokines], [chemokines], and [extracellular matrix proteases]. Significantly contributes to aging and cancer. Data shows it also plays a role in atherosclerosis, type 2 diabetes, skin aging and osteoarthritis. Senescent cells express higher levels of [pro-survival genes] → highly resistant to apoptosis. - - - Possible approaches besides removal: - - **[8. Stem cell exhaustion:]** Every cell has the same genetic code, but different DNA sections are turned off and on in each one → different cell types. Stem cells can change their epigenetics → turn into different types. Stem cell functions: - - **Stem cell exhaustion** = reduction in stem cell activity → immunosuppression (reduced white blood cell production), muscle loss, frailty, and the weakening of bones. Reasons for stem cell exhaustion with increasing age: - - - Pool of stem cells regenerates itself with lower quality and speed over time → chronic diseases. Early stem cell research: cells harvested from early-stage embryos. Now: turning adult cells back into stem cells. **Induced pluripotent stem cells (iPSCs;** created by Shinya Yamanaka). **Yamanaka factors =** chemicals that influence cells into becoming stem cells. Stem cell research = most mainstream of research topics in the aging field and well-funded: - - - **[9. Altered intercellular communication:]** Signaling between cells becomes more inflammatory with age → inhibits the immune system → **inflammaging**. Causes: - - Inflammaging → cells increasingly activate a chemical in their nucleus called **nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)**. NF-kB regulates the production of proteins, enzymes, and local signals (cytokines). a. b. Example: NF-kB is activated in the hypothalamus → inhibits the production of gonadotropin-releasing hormone (GnRH) → reduced signaling to other bodily system → bone fragility, muscle weakness, skin degradation, and other harmful effects. - - Apheresis: blood removed → pro-aging signaling molecules removed → blood is reintroduced. Attempt at mimicking the effect of parabiosis.