Hallmarks Of Aging. The 9 Different Signs & Their Connection to NAD+

What are hallmarks of aging?

Its have been everyone’s desire to stay young and stop or at least slow down the aging process, and  It’s no surprise that we make frequent mention of the hallmarks of aging — and with good cause.

Evolutionary Biology of Aging described aging as “a sustained fall in the age-specific fitness components of an organism due to internal physiological degradation” in 1991. Specific cellular processes begin to break down as we grow older. They are the aging processes we all go through in our lifetime. Groundbreaking research was published a few years ago that identifies some of these cellular processes that will be discussed today in this article. They were named Hallmarks of Aging.

The paper was published in 2013, laying 9 hallmarks of aging. It was authored by Carlos Lopez-Otin, a Biochemistry and Molecular Biology professor at the University de Oviedo in Spain. This publication started a revolution in longevity research by providing the framework for a new way of seeing aging as a process of cumulative cellular damage over an extended period. Damage may be mitigated or reversed, leading to rejuvenation and an extension of longevity and health span. This discovery has also fueled the efforts of several scientists to conquer the aging process and the growth of new bio-health enterprises devoted to the fight against aging.

  1. Epigenetic Alternations
  2. Loss of Proteostasis
  3. Deregulated Nutrient Sensing
  4. Mitochondrial Dysfunction
  5. Cellular Senescence
  6. Stem Cell Exhaustion
  7. Altered Intercellular Communication
  8. Genomic Instability
  9. Telomere Attrition

This research paper identified 9 fundamental hallmarks of aging, which were further divided into three categories. hallmarks of aging

Image Source: first category was called primary hallmarks of aging. They are called primary because they’re the ones who cause the initial damage. These hallmarks are interrelated, affecting each other in a vicious cycle, and may also involve different types of hallmarks downstream.

The next category is called compensatory or response hallmarks of aging. They are named because they either respond to physiological changes to primary hallmarks or as a way of compensating them. So stopping the primary hallmarks could reduce the onset of these compensatory hallmarks.

The third category is called integrative hallmarks, and these are downstream to both primary and secondary hallmarks. These hallmarks of aging lead to a decline of multiple bodily functions and cellular processes. So stopping primary or secondary hallmarks could impact any hallmarks downstream.


1. Genomic Instability

The first of the hallmarks of aging is called genomic instability. The DNA is your body’s blueprint, providing specific instructions for each process. Our cells recognize the value of DNA, encasing it in solid walls to keep it secure from destructive influences. No matter how hard your cell tries, its DNA is being attacked. Free radicals, and free radical generating substances (pollution, pesticides, and the sun’s UV rays..etc.) all cause harm to your DNA.

The American Federation of Aging Research estimates that your DNA is damaged one million times every day.

Additionally, DNA encodes a set of instructions for repairing itself in the presence of such aggressors, although this repair is limited. As you age, damage to your DNA (or genome) accumulates, referred to as genomic instability. The processes become weak with aging and become less efficient, and these errors add up, leading to dysfunctional cells.

2. Telomere Attrition

Telomeres are protective caps at the ends of chromosomes, resembling shoelace caps. Every time your cells divide, a portion of your telomeres is thrown off, making them shorter and shorter. The telomeres eventually run out of the runway, and there is no more room to trim. At this time, the cells cannot divide, which accelerates the aging process. Because telomere length is finite, researchers examined in 2019 their association to estimate lifetime. The results suggest that a species’ telomere shortening rate can predict its life duration. Telomere shortening can lead to instability of the genome and is the leading cause of cellular senescence and regarded as one of the most important hallmarks of aging.

3. Epigenetic Alternations

The epigenome is a collection of chemical molecules that instruct your DNA on behaving. If DNA serves as the architect for your body, your epigenome serves as the contractor. They make the decisions on what to develop. This process is sometimes referred to as gene expression. Environmental factors and diseases can affect our epigenome as we age. They are the leading cause of genomic instability, according to a recent article published in the Journal of Applied Physiology. These changes may affect how your epigenome regulates gene expression, affecting how your DNA is processed. Epigenetic alternations are not permanent, so they can be reversed. One particularly well-studied group of molecules that influence the epigenome is the sirtuins.

4. Loss of Proteostasis

Proteostasis is derived from the root terms “protein” and “stasis,” both of which refer to a condition of equilibrium. Proteins are a large group of molecules that regulates almost everything in the body. They are composed of millions of small molecules known as amino acids. The manner a protein function is determined by the way these amino acids are connected or folded. These folds will dictate which genes are expressed.

Proteostasis is maintained in your body by a network of proteins, although faults can occasionally result in the creation of insufficient or excessive proteins. These errors may result in network folds, disrupting the order and resulting in miss-shaped and dysfunctional proteins. Proteins that are misfolded will be unable to perform their given function properly, resulting in suboptimal performance. Additionally, these proteins can be linked together, producing an aggregation and inflicting additional damage and won’t be filtered out of the body due to the slower process of aging.


Also known as response hallmarks, they result in compensation and physiological changes due to primary hallmarks.

5. Deregulated Nutrient Sensing

Our cells require nutrients to function properly, which they obtain from the food we eat. And to sense which the body requires nutrients, we have several nutrients sensing pathways such as mTOR and AMPK that make sure we get enough nutrients and they also guarantee that we don’t consume too much or too little food. However, as oxidative stress damages our cells, these sensors have problems controlling your nutritional intake, some of them get cranked up, or some may turn down thus reducing longevity.

6. Mitochondrial Dysfunction

The mitochondria are the cell’s “powerhouse.” They provide all of the energy in the form of ATP required by your cells, acting as the fundamental component of metabolism. The mitochondria generate 90% of the energy in our body. As we age, the mitochondrial population also decreases, and individual mitochondria become less efficient at producing ATP, this depletion and reduction severely impact the amount of energy available. This causes bodily functions to slow down or function improperly in the worst situations. It then causes cellular damage and accumulation.

7. Cellular Senescence 

Senescence is state in which cell loses its ability to divide, resulting in its abrupt end. The senescence of cells is a normal process. Generally, our body can generate sufficient new cells to outnumber senescent cells. The amount of senescent cells, on the other hand, grows with age and accumulates inside the body causing damage by releasing inflammatory cells. This process leads to reduce tissue repair and other hallmarks of aging. 


These hallmarks lead to functional decline and are downstream of the above-mentioned hallmarks of aging.

8. Stem Cell Exhaustion

As we are already aware that our cells have a purpose. Skin, liver, brain, and heart cells all have the same purpose and their roles are assigned by the epigenome. But stem cells are like new grads ready to join the cellular industry. They don’t have a specific work yet and are eager to take on more. To meet your body’s needs, stem cells can self-identify. Consider them as cellular reinforcements. For example, if more liver cells are needed, stem cells will specialize to become liver cells.

This cell replenishment cycle is essential to preserving tissue homeostasis and regeneration. Stem cell exhaustion occurs when this newly formed workforce is unable to replace retiring cells at a rate sufficient to maintain optimal tissue function. Stem cell exhaustion is also related to other hallmarks of aging, as the imbalance between stem cells and retiring cells can emerge due to senescent cell multiplication, which is mainly caused by DNA damage.

9. Altered Intercellular Communication

All the cells in the body are in continuous communication with each other with the help of chemical messengers. But as you age, this massive communication network loses signal. Altered intercellular communication occurs when the signals diminish. But with aging the inflammation distress signals are produced which causes damage to other tissues. Inflammation is your body’s natural defense mechanism for removing pathogens and damaged cells. However, inflammation can occasionally go beyond its intended short-term effect and inflict considerable damage to neighboring healthy cells. One of the primary reasons is the presence of senescent cells, which are no longer capable of replication. Senescent cells produce inflammatory substances, which wreak havoc on the cell environment.

Understanding all of these processes, including what they are, how they function, what causes them, and how to manage them, is essential for anybody who wishes to turn back the clock. What can be the solution to longevity / anti-age?


NAD+, nicotinamide adenine dinucleotide, is being investigated as the main cause of the hallmarks of aging. The human body is composed of 30-40 trillion cells, and each of them is dependent on a coenzyme called nicotinamide adenine dinucleotide (NAD+) in order to function properly and perform daily functions.

NAD+ is a major element of health and wellness.

NAD+ levels decrease as we become older. These changes play an important part in the development of age-related illnesses such as diabetes, Alzheimer’s disease (together with its complications), obesity, heart disease, and loss of muscle tone. NAD+ levels decrease with age for two key reasons. To begin, as we age, our bodies produce fewer NAD+. Second, inflammation, oxidative stress, and faulty DNA all deplete the body of NAD+. As a result, a variety of biological activities that rely on NAD+ are disrupted.

There is a direct correlation between NAD+ level in the body and the state of health at each age. These characteristics are at the heart of how the body ages.


David Sinclair, a well acclaimed genetic researcher professor at Harvard University, believes that aging is a disease that can be cured. Learn more about his findings and methods to anti-age here. Dr. Sinclair expressed that the key to longevity is to activate sirtuins, AMPK and to inhibit mTOR. Dr. Sinclair and other scientists from all around the world have been focusing on whether increasing NAD+ levels in the body by supplementation (with precursor of NAD+ such as NMN and anti-inflammatory molecules such as Resveratrol), can be the key to slow or even to reverse the effects of aging, and the associated diseases, allowing people to live longer, healthier lives.

In this section, you’ll have a glimpse about the role of NAD+ in numerous aging characteristics and how increasing NAD+ levels in the body may help to counteract and enhance the consequences of aging.

Repair Of Damaged DNA

A reduction in NAD+ impairs the cell’s ability to divide and makes it more difficult to repair DNA. According to the findings of the study, supplementing NAD+ in aged mice boosted the cell’s ability to repair DNA damage.

Increasing The Sirtuins Activity

Sirtuins are a family of proteins involved in metabolic regulations and are responsible for protecting the length and function of telomeres. Among their various roles, sirtuins are involved in the regulation and delay of cellular aging – and their proper function is dependent on the presence of NAD+. ( 1 ) ( 2 ) ( 3 ). According to animal studies, increasing NAD+ levels is connected with an increase in sirtuin activity. Enhancing sirtuin activity helps to stabilize telomeres, prevent DNA damage, and ameliorate the conditions that are dependent on telomeres.

Improvement in Cellular Senescence

Increasing the levels of NAD+ in older mice has been found to renew and prevent the senescence of muscle stem cells, as well as to increase the total longevity of the mice. Pretreatment with the NAD+ resulted in an increase in the mitochondrial unfolded protein response and the synthesis of prohibitin proteins, which resulted in the rejuvenation of cellular sciences in elderly mice.

Another study carried out in 2020 made its way to human cells showing boosting NAD+ levels may benefit human mesenchymal cells.

Regeneration of Stem Cell

Numerous studies have now demonstrated that extrinsic stimuli can resurrect stem cell function, paving the way for the prospective pharmaceutical prolonging of stem cell health. Stem cell loss due to cell malfunction or senescence may contribute to biological aging. Hongbo Zhang and colleagues recently demonstrated that activating the mitochondrial unfolded protein response, a retrograde stress response, can regenerate stem cells and lengthen lifespan in mice.

Physical Exercise & Hallmarks of Aging

Exercise offers a number of benefits as per research on all the hallmarks of aging, one of which is through increased NAD (nicotinamide adenine dinucleotide) levels, which activate the survival network of longevity regulators such as AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and sirtuins.

NAD+ boosting therapies are a near-future possibility, as they are now in small-scale human trials, to progress to more extensive human trials in the future. This therapy can be considered a proper rejuvenation treatment because it directly targets the aging hallmark of dysregulated nutrient-sensing and partially addresses genomic instability by stimulating DNA repair. It will be interesting to watch if this or senescent cell clearance becomes the next rejuvenation technology to emerge, given the success of stem cell therapy.

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Being a Doctor by profession, Aimen is passionate about helping people get better health in their lives. Aimen enjoys her research on Prime With Time subjects and strives to create better awareness of the problems and changes related to women's health.

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