Answering the Big Questions about Aging

Developments in life expectancy and the growing emphasis on biological and ‘healthy’ aging raise some important questions.

Aging, one of the many elephants in life’s room, is a complex issue. We can’t just look at someone’s DNA and predict how long they will live (lifespan) and how many years they will spend in good health (healthspan). You might also resort to fortune-telling methods like interpreting patterns in tea leaves, coffee grounds, or wine sediments.

To get a sense of how well a person is aging, you will have to include more aspects of what goes on in their lives, like what they put into their bodies, how much money they make, where they’re from, and more.

Although linked to how old you are, biological aging does not reflect how many days you’ve been alive. Instead, it has to do with the health and state of everything that you comprise, from molecules and cells to tissues, organs, and your body as a whole.

What’s the difference between aging and longevity?

Healthy aging is not to be confused with longevity. The number of years we age in good health, called healthspan, is intimately tied to how long we live, lifespan; but these concepts are not the same. This distinction is crucial for adequately describing the unprecedented lengthening of lifespan without significant healthspan changes, which has left people susceptible to more extended periods of poor health.

Why do we age?

The struggle with our mortality and the inevitable aging fate goes back to some of the earliest history recordings. Many of us have cursed in angst about our limited existence. Researchers have sliced and diced this concept with all sorts of theories. Generally, these can be broken down into programmed and error theories of aging.

Programmed theories of aging:

Programmed theories assert that the human body, like a wind-up clock, is designed to age and follow a biological timeline. All of these theories share the idea that aging is natural and encoded into the body. There are a few different programmed theories of aging:

• Genetic theory: the idea that aging is caused by specific genes switching on and off over time.
• Endocrine theory: the idea that regular changes in hormones control aging.
• Immunological theory: states that the immune system is programmed to decline over time, leaving people more susceptible to degenerating health.

Error theories of aging:

Error theories assert that aging is caused by damage to the body’s systems that collect over time. Some researchers posit that the underlying cause is mainly the accumulation of unrepaired molecular damage over time. Eventually, this leads to cellular defects and tissue dysfunction, increasing frailty and age-related medical conditions.

Our cells possess quality control systems so that molecular damage can be recognized, repaired, or removed. But all molecular components (DNA, proteins, and lipids) as well as the cell’s “organs,” called organelles, are susceptible to damage. We now know of some key events at the molecular level that are tied to aging:

• DNA damage and repair: DNA is susceptible to damage. External stressors, such as UV light and radiation, as well as internal ones like oxidative stress (see below), constantly bombard our DNA, which can lead to errors in our genetic sequences. Most damage to DNA is detected and repaired, but more complex lesions may remain unrepaired, and the accumulation of such lesions may negatively affect cell health and longevity.
• Telomere shortening: Telomeres are repetitive sequences of DNA that protect the ends of linear chromosomes. In human cells, telomeres shorten with each cell division, a process that has long been linked to aging. Once telomeres hit a critical length from this shortening process, they can trigger aging at the level of cells. 
• Loss of protein balance: Protein regulation is crucial for cellular function. Proteins are assembled from strings of amino acids that get folded into 3D molecular machines to carry out many of the functions of the cell. Optimal protein levels are maintained by quality control systems involved in protein synthesis, folding, and refolding.
• Chaperone saturation: Some protein damage may be repaired by molecular chaperones that bind to the exposed hydrophobic surfaces and assist in refolding. However, it has been proposed that the chaperone system becomes overwhelmed with age, leading to a further increase in damaged or misfolded proteins.
• Mitochondrial damage: The power plants of our cells, mitochondria, can also be central to aging. The accumulation of damaged mitochondria is tied to aging. These damaged mitochondria can become dangerous sources of internal stress that can damage other molecules.

One primary driver of these damaging molecular events is oxidative stress, which is the accumulation of reactive oxygen species (ROS) due to inefficient or ineffective detoxification of these harmful molecules. Oxidative stress leads to damage to DNA and changes in proteins and lipids in the cell. The cell ultimately loses its functionality and dies. Over time, the tissue suffers, and the body ages. This is one of the reasons why there has been so much hype about anti-oxidants

What is cellular senescence?

In 1961, two researchers, Hayflick and Moorhead, first described cellular senescence. They showed that human cells in culture do not divide indefinitely but reach a limit (called the Hayflick limit) of replication and stop further division. Cells approach this limit by slowing their divisions and entering cellular senescence, a dormant state fueled by self-perpetuating pro-survival and anti-death signals.

Cellular senescence also has harmful effects as it can hinder tissue repair and regeneration, contributing to aging. Senescence can be triggered by molecular aging and propagated by signals that senescent cells send out to the environment, luring them into the same trance.

Research shows that removing senescent cells can influence aging and longevity. The sensitivities of senescent cells to pharmacological treatments called senolytics that can promote their death are diverse. Some are synthesized in labs, and other senolytics are naturally occurring, such as quercetin and fisetin.

What factors influence aging?

Broadly speaking, factors linked to aging can be divided into six categories:

• Biological: Physiological (e.g., body mass, sleep patterns, and stress) and biochemical (e.g., levels of hormones, metabolites, and immune signaling molecules).
• Mental: Cognitive characteristics (e.g., life satisfaction).
• Behavioral: Individual lifestyle choices (e.g., physical activity, alcohol consumption, smoking, and polypharmacy).
• Nutritional: diet (e.g., food, vitamins, and supplements).
• Socioeconomic: Quality of life attributes as well as the opportunities and privileges afforded to people within society (e.g., education, occupation, and wealth).
• Environmental: Exposures (e.g., air quality, water safety, and war).

What effects does an aging society have?

Over the past two centuries, we’ve seen a significant increase in lifespan. With this, the global proportion of older people (aged 60 or above) is rising. Some estimates project that the proportion of older people will nearly double between 2020 and 2050. What’s more, the ’oldest-old’ (people aged 80 or above) group is estimated to triple in the same time period.

The increase in the aging population brings many challenges. Although many welcome the prospect of an increase in lifespan, this needs to be accompanied by an increase in healthy years rather than further years with poor health. Furthermore, there is a wide variation in the health among older individuals, with some 80-year olds having the same physical and mental capacity of many 20-year olds. In contrast, other individuals experience a decline in physical or psychological ability at much earlier ages.

The future of aging

Many researchers studying aging, a field that has been labeled geroscience, believe that aging can be halted and even reversed. Improving aging can have a huge benefit not just on how people experience and enjoy life from a health perspective, but it can also have major economic effects. Central to much of the research in geroscience is the concept that manipulating fundamental aging mechanisms will expand healthspan by going after the underlying risk factor — namely, aging.