Science Of Aging

Hallmarks of Aging

The human body contains trillions of cells that work together, fueled by a metabolism comprised of thousands of processes. In such a complex system, aging seems to be intractable. However, in recent years, scientist have come up with a small list of causes that can explain the aging process, the nine hallmarks of aging.

1 Genomic Instability

One common denominator of aging is the accumulation of genetic damage throughout life. Mutations can affect essential genes and transcriptional pathways, resulting in dysfunctional cells. DNA damage impacts both matured cells and stem cells, compromising their role in tissue renewal. The evidence for the proposed links between lifelong increase in genomic damage and aging comes from studies in mice and humans. These studies show that deficiencies in DNA repair mechanisms cause accelerated aging in mice and underlie several human genetic disorders that cause premature aging. Furthermore, genomic instability affects both the nuclear and mitochondrial DNA of a cell (see below to learn more about mitochondria).

Thankfully, there is evidence that if we improve the machinery that helps keep chromosomes healthy, we can extend longevity in mammals.

2 Telomere Attrition

A telomere is a region of DNA at the end of a chromosome that protects the chromosome from degradation or from fusion with neighboring chromosomes. Telomeres are essential for proper chromosome function, and their length is an important marker of cellular age. They are like the ends of shoelaces, getting shorter each time a cell divides. Once there are no more telomeres, the cell can’t divide anymore; thus limiting the number of times a cell can divide. Telomere shortening is associated with aging and certain diseases. Genetically modified animals have been used to study the effects of telomere length on aging. Mice with shortened telomeres live shorter lives. In humans, short telomeres have been linked to an increased risk of mortality, especially at younger ages.

There is evidence that aging can be reversed by activating telomerase. Telomerase is an enzyme that helps to lengthen telomeres.

3 Epigenetic Alterations

Epigenetic changes are changes that turn genes on or off, and these changes can be caused by the environment, lifestyle, and age. Often, they are characterized by changes in methylation patterns; methylation is when a molecule is chemically modified by the addition of a methyl group as a marker.

Epigenetic changes are theoretically reversible, which means they could be used to treat aging. This is different from DNA mutations, which are changes to the DNA itself and mostly can't be reversed.

4 Loss of Proteostasis

The proteome is the complete set of proteins that are produced by a cell or organism. Proteins are the main functional molecules in cells and perform a wide variety of functions. The proteome is constantly changing in response to the needs of the cell or organism. Aging and some aging-related diseases are linked to impaired protein homeostasis or proteostasis. This means that the cells have a harder time preserving the stability and functionality of their proteins as we age. Chronic expression of unfolded, misfolded, or aggregated proteins contributes to the development of some age-related pathologies, such as Alzheimer’s disease, Parkinson’s disease, and cataracts.

Approaches for maintaining or enhancing proteostasis aim at activating protein folding and stability mediated by chaperones and/or by enhancing autophagy (learn more in our “deep dive”).

Deep dive

Proteostasis involves several mechanisms for the stabilization of correctly folded proteins and mechanisms for the degradation of proteins:

Chaperones are proteins that help other proteins to fold correctly into their proper three-dimensional structure. Several approaches for maintaining or enhancing proteostasis aim at activating protein folding and stability mediated by chaperones, such as the heat-shock protein family. A heat-shock protein is a chaperone that is produced by cells in response to exposure to stressful conditions, such as high temperatures.
Proteasomes are protein complexes that help to break down proteins in cells. They are found in all eukaryotic cells and are essential for the proper functioning of the cell. The proteasome is responsible for the degradation of proteins that are damaged or no longer needed by the cell. In such a case the protein is tagged for destruction by a process called ubiquitination. The proteasome then breaks down the protein into small peptides that can be used by the cell for energy or other purposes.
Autophagy is the process of cell self-digestion, whereby cells break down and recycle their own components. This process is important for maintaining cell health and preventing the accumulation of damaged molecules and organelles. Lysosomes are organelles within cells that contain enzymes that break down macromolecules. The autophagy-lysosomal system uses lysosomes to break down and recycle damaged or unnecessary parts of cells.

5 Deregulated Nutrient Sensing

There are different metabolic pathways in the cell, that signal either scarcity or abundance of nutrients through nutrient sensors. Generally spoken and somehow simplified, one could say that nutrient abundance and anabolic activity are major accelerators of aging whereas signals of nutrient scarcity and catabolism favor healthy aging. As we age, nutrient sensing becomes more and more deregulated.

Deep dive

IIS pathway (activation favors accelerated aging)
The so-called somatotrophic axis is a pathway in mammals that includes the growth hormone (GH) and the insulin-like growth factor 1 (IGF-1). GH is produced by the anterior pituitary, which is a hormone producing gland in the brain. IGF-1 is produced in response to the GH by many cell types, most notably liver cells. The intracellular signaling pathway of IGF-1 is the same as that elicited by insulin, which tells cells about the presence of glucose. For this reason, the IGF-1 and insulin signaling are known as the “insulin and IGF-1 signaling” (IIS) pathway. The IIS pathway is the most conserved aging-controlling pathway in evolution, meaning that it is found in many different species, and among its multiple targets are the FOXO family of transcription factors and the mTOR complexes, which are also involved in aging. Genetic polymorphisms or mutations that reduce the functions of the IIS-Pathway have been linked to longevity, both in humans and in model organisms, further illustrating the major impact of trophic and bioenergetic pathways on longevity.
mTOR pathway (activation favors accelerated aging)
mTOR is a nutrient-sensing enzyme that senses high amino acid concentrations. It plays a key role in regulating cell growth, cell proliferation, and cell survival. mTOR is a central regulator of cell size, and it has been shown to be involved in the control of cell cycle progression and cell death. mTOR stands for “mechanistic target of rapamycin”. Rapamycin is a drug that in mice extends longevity in what is considered to be the most robust chemical intervention to increase lifespan in mammals.
AMPK pathway (activation favors healthy aging)
AMPK is an enzyme that plays a role in regulating energy balance in the body. When energy levels are low AMPK is activated and helps to restore energy balance by stimulating processes that generate ATP (the energy currency in the body) and by inhibiting processes that use ATP. AMPK also regulates other important cellular processes such as cell growth, cell death, and inflammation. AMPK activation has multiple effects on metabolism and, remarkably, shuts off mTORC1. There is evidence indicating that AMPK activation may mediate lifespan extension following metformin administration to worms and mice (metformin is a drug used to treat diabetes)
Sirtuins (activation favor healthy aging)
A sirtuin is a type of protein that is found in a variety of organisms, from plants to humans. In humans, sirtuins are involved in many different processes, including metabolism, cell death, and inflammation. They sense low-energy states by detecting high NAD+ levels. Sirtuins have been shown to play a role in the aging process, and some researchers believe that they could be potential targets for anti-aging therapies. This idea comes from studies done on yeast, flies, and worms, which found that a protein called Sir2 (which later became the name giver for ”Sirtuins”) seemed to make these organisms live longer. However, some recent studies have questioned these findings. Nevertheless, it seems that several of the seven mammalian sirtuin paralogs can improve various aspects of aging in mice, including genomic stability and enhanced metabolic efficiency.

6 Mitochondrial Dysfunction

Mitochondria are organelles in the cells of plants and animals that are responsible for energy production. These organelles are often referred to as the “powerhouses” of the cell. Mitochondria are unique in that they have their own DNA separate from the DNA in the cell nucleus. This DNA is used to produce proteins that are essential for the function of the mitochondria. The mitochondrion contains several important enzymes that are responsible for the production of ATP, the energy currency of the cell. There has been a long-standing suspicion that mitochondrial dysfunction is related to aging, but researchers have yet to fully understand the details of this connection.

Deep dive

The mitochondrial free radical theory suggests that aging is caused by progressive mitochondrial dysfunction that results in increased production of reactive oxygen species (ROS). ROS are highly reactive molecules that can cause damage to cells and tissues. However, recently it has been observed that increased ROS may actually prolong lifespan in certain organisms. These findings have led to a reconsideration of the role of ROS in aging. It is now believed that ROS may be a stress-elicited survival signal that activates compensatory homeostatic responses, called hormesis. However, beyond a certain threshold, ROS levels will aggravate age associated damage. Furthermore, it is important to understand that dysfunctional mitochondria can contribute to aging independently of the presumed increase of ROS. Interestingly, endurance training and alternate day fasting may improve healthspan by reducing mitochondrial degeneration.

7 Cellular Senescence

Senescent cells are cells that have stopped dividing and are in a state of permanent cell cycle arrest. This was originally described by Hayflick in human fibroblasts serially passaged in culture. Today, we know that the senescence observed by Hayflick is caused by telomere shortening, but there are other aging-associated stimuli that trigger senescence independently of this telomeric process. Senescent cells accumulate over time with age and are thought to contribute to the age-related decline in tissue function. While senescent cells do not divide, they remain metabolically active and some of them secrete a range of pro-inflammatory cytokines and growth factors that can promote age-related chronic inflammation and cell death. These cells are called the senescence-associated secretory phenotype (SASP).

Understanding the role of cell senescence in aging is challenging. While the SASP can have a profound detrimental effect on tissues and may accelerate aging, cellular senescence can also be a beneficial response to cell damage helping to prevent further damage.

8 Stem Cell Exhaustion

Stem cells are cells in our bodies that can turn into other types of cells. They act as a reserve pool of cells, and also help us repair damage and keep our bodies healthy. The decline of stem cells and therefore, the regenerative potential of tissues is one of the most obvious characteristics of aging in multiple tissues. This means that as we get older, our tissues don't have the same ability to regenerate or heal as they did when we were younger. For example, hematopoiesis (the formation of blood cells) declines with age, resulting in diminished production of immune cells – a process called immunosenescence. The attrition of stem cells correlates with the accumulation of DNA damage and with the overexpression of cell-cycle inhibitory proteins. Telomere shortening is also an important cause of stem cell decline with aging. These are just examples of a much larger picture in which stem cell decline emerges as the integrative consequence of multiple types of damage. Some studies suggest that we may be able to reverse the aging process by rejuvenating our stem cells.

9 Altered Intercellular Communication

Aging leads not only to changes on individual cell levels, but also to changes in the way cells communicate with each other. This communication can happen in different ways, for example by sending hormones or other signals. Often, these signaling systems don't work as well in older age. A prominent aging-associated alteration in intercellular communication is “inflammaging”, which is a smoldering proinflammatory phenotype that accompanies aging in mammals. Inflammaging may result from multiple causes, such as the accumulation of proinflammatory tissue damage, the failure of an ever more dysfunctional immune system to effectively clear pathogens and dysfunctional host cells, and the propensity of senescent cells to secrete proinflammatory cytokines. Scientists have found that by inhibiting inflammatory pathways, they can cause some of the physical signs of aging to be reversed. This has been shown in different mouse models of accelerated aging.