The Aging Response — How You React to Aging and What To Do About It, Part 2

Image credit: Crvitality.com

This piece on aging response hallmarks follows on the heels of Part 1, The 4 Reasons We Age and What To Do About It. We continue with reviewing Dr. Carlos Lopez-Otin and his team of researchers who authored a seminal paper on aging called, The Hallmarks of Aging.

Whereas in Part 1, the focus was on the Primary reasons we age, here we’ll investigate the three Antagonistic (or Compensatory) and two Integrative reactions to the Primary category. Importantly, we’ll also look at what interventions can be done to slow down the degradation that is aging with the aim of extending our healthspan, if not our lifespan.

This is a long and dense look at the science of aging. If you find yourself faltering, scroll down to the bottom and read the bottom line in “Your Takeaway”.

Here’s what we’re going to cover:

• How the Hallmarks of Aging interrelate.
• Deregulated Nutrient Sensing — how metabolism becomes imbalanced.
• Mitochondrial Dysfunction — why the body’s energy factory falters.
• Cellular Senesence — what zombie cells do to us.
• Stem Cell Exhaustion — no more tissue and cellular renewal.
• Altered Cellular Communication — you just don’t understand me anymore.

In each section, I’ll explain the science a bit and what interventions are available for you to try.

Let’s dig in…

 

Summary of the Hallmarks of Aging — How they interrelate

As was done in Part 1, it’s helpful to set the stage for what’s to come by quickly reviewing the nine characteristics (hallmarks) of aging as discerned by Dr. Carlos Lopez-Otin and his research team in their classical work, The Hallmarks of Aging.

These hallmarks are shown in this graphic, which show an interconnected, hierarchical relation between them, as discerned by Dr. Carlos Lopez-Otin’s team:

This is Figure 6 from The Hallmarks of Aging study

Primary Hallmarks of Aging

The common characteristic of the Primary hallmarks is that they are all unequivocally negative, and are considered to be the initiating triggers whose damaging consequences progressively accumulate with time.

Part 1 was devoted to the four Primary hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations and loss of proteostasis.

Antagonistic/Compensatory Hallmarks of Aging

In contrast to the Primary, Antagonistic hallmarks have opposite effects depending on their intensity. At low levels, they mediate beneficial effects, but at high levels, they become deleterious.

Here are three examples stemming from their respective hallmark categorization:

1. Degregulated nutrient sensing — Optimal nutrient sensing and anabolism are important for survival, but in excess and over time can become pathological.
2. Mitochondrial dysfunction — ROS (referring to Reactive Oxygen Species, or “free radicals”) mediate cell signaling and survival, but at chronic high levels can produce cellular damage.
3. Cellular senescence — Senescence protects us from cancer, but if excessive can promote aging.

Antagonistic hallmarks can have the capacity to protect us from damage or from nutrient scarcity; however, when exacerbated or chronic, their purpose is subverted and they generate further damage.

Integrative Hallmarks of Aging

The third category comprises the two Integrative hallmarks that directly affect tissue homeostasis and function:

1. Stem cell exhaustion, and
2. Altered intercellular communication.

These Integrative hallmarks arise when the accumulated damage caused by the Primary and Antagonistic hallmarks overwhelm tissue homeostatic mechanisms (body cell/tissue regulation), and thereby can not give compensating effects.

What this means: Cells must adapt to nutrient characteristics and quantities. If such adaptions are compromised, a cascade of health issues will occur.

What’s Deregulated Nutrient Sensing? Nutrient sensing is a cell’s ability to recognize and respond to food/fuel such as glucose. It has an essential role in maintaining cellular homeostasis (balance) by regulating downstream metabolic processes. When “deregulated” at least four metabolic pathways are negatively affected.

What you need to know:

• Each type of fuel used by the cell requires an alternate pathway of use and accessory molecules. In order to conserve resources a cell will only produce molecules that it needs at the time. (1)
• As we age, cells become less right at detecting the amount and type of food/fuel available to them. This can affect, for instance, four vital protein groups and their associated pathways; namely: IGF-1, mTOR, sirtuins, and AMPK. These proteins are referred to as “nutrient sensing” because nutrient levels influence their activity. (2)
• Caloric mimicking diets — such as various types of Intermittent Fasting and the Prolon Fasting Mimicking Diet — may improve, or upregulate, nutrient sensing pathways and even reverse diabetes. (3, 4)

The aging response is a process of degeneration. What we see in our aging bodies is simply the physical manifestation of decades of accumulated damage to our nutrient sensing pathways. Over time, metabolic activities place increasing stress on our cells. Too much food intake or the wrong nutrient composition causes cells to age faster.

Our brain’s hypothalamus also becomes dysfunctional, leading us to eat more than the body needs, potentially resulting in metabolic syndrome, obesity, and type 2 diabetes. To make things worse, obesity and diabetes provoke chronic inflammation, which can further deregulate our nutrient sensing system.

Because metabolic pathways are intertwined with longevity pathways, geroscientists have focused on them in their search for anti-aging treatments.  Caloric restriction continues to be a leading anti-aging intervention.

The most studied type of calorie restriction is an indefinite +/- 30% reduction in ingested calories from a baseline amount of calories relative to an organism’s size.  Studies with worms, rodents and monkeys have shown an increase of healthspan and lifespan through a sustained reduction of calories. (5, 6, 7)

It’s harder to do longevity studies on long-lived humans than animals/organisms with lifespans of a few weeks (worms) to twenty years (monkeys); however, sustained caloric reduction in humans has been shown to improve various biomarkers associated with aging, such as the inflammatory cytokines profile, adiponectin/leptin ratio, insulin and IGF-1, and thereby is considered a robust life extension protocol. (8)

Credit: Crvitality.com

The bad news is that nearly no one is willing to suffer through a lifetime of sustained restriction of caloric intake of 30% or more, no matter what the reward. The good news is that intermittent caloric restriction can “mimic” the health and longevity benefits of sustained calorie deprivation without the difficulty, for it’s easier to restrict calories during intervals than forever.

(For more on the benefits of CR restriction, read this on CR Vitality.)

What You Can Do

As just mentioned, research studies show that caloric restriction and forms of intermittent fasting such as the Fasting Mimicking Diet (FMD) can extend human lifespan, as they do with worms, fruit files, rodents and monkeys.

Dr. Valter Longo is among the world’s top experts on the health and longevity aspects of “fasting diets”. His research has led him to develop the Prolon Fasting Mimicking Diet, which has demonstrated improvements in the aging response of several health and aging-related biomarkers, as well as weight loss. (9, 10, 11)

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What this means: Cells are stressed and damaged their aging response is to become zombie cells, meaning they are not fully alive nor dead.

What’s Cellular Senescence?  It’s when normal cells stop dividing and properly function, but are still alive.

What you need to know:

The number of senescent cells increases with aging, leading to the widely held assumption that senescence contributes to the aging response. This view, however, undervalues what is conceivably the primary purpose of senescence — to prevent the propagation of damaged cells and to trigger their demise by the immune system. Therefore, it’s possible that senescence is a beneficial compensatory response that contributes to rid tissues from damaged and potentially oncogenic (cancerous) cells.

But there’s a catch.

Senescent cells’ secretions (secretome) are rich in two types of proteins, the proinflammatory cytokines and matrix metalloproteinases (referred to as the ‘‘senescence-associated secretory phenotype’’) which Dr. Jean-Philippe Coppé et al refer to as the “dark side of tumor suppression”. This is because although cellular senescence is tumor-suppressive mechanism that permanently arrests cells at risk to become malignant, such cells also can have deleterious effects on the tissue microenvironment, which become increasingly detrimental as we age. (23)

Clearly, senescent cells accumulate with time and age, and promote age-related disease. Scientists have found that eliminating senescent cells in old mice seems to reverse some of the effects of aging. And the opposite is also true — when senescent cells were injected into young mice, they had debilitating and inflammatory effects, and were harmful to overall health. (25)

What You Can Do

Scientists have made tremendous progress in developing senolytics that clear senescent cells from the body My report on senolytics discusses the efficacy of several compounds geroscientists have discovered that clear senescent cells and slow the aging process. Several of these compounds are slated for clinical trials. (26)

Three senolytics widely available are: Quercetin, Piperlongumine and Fistein.  Fistein may be the most potent of the three. (27)

Life Extension offers a promising senolytic-activators, called (what else) Senolytic Activator.