The average human lifespan is currently 72 years. Men average 69.8 years while women average 74.2 years, though women have much shorter reproductive capability than men. Since ancient times there have always been myths and legends about sources of eternal youth. There have been healers, and snake oil salesmen, true scientists and physicians that have claimed to improve lifespan, healthspan and fertility. Indeed, expectancy has increased dramatically since 1900, but we must beware of fraud. Even now, and in the future, advances in the fields of organ transplants, implantable devices, artificial limbs, and artificial intelligence have already begun to push the limit of available therapies; but access to experimental treatments, and the overall cost of certain types of interventions will create questions about access to care for ordinary diseases of aging. To achieve life extension without healthspan expansion would be pointless. Ideally we want to be healthy for as long as possible and then die quickly, avoiding the ravages of chronic disease. What is the current research on what can be done to extend healthspan (and hopefully life span) right now? Are there any drug treatments that show promise? What are the most important lifestyle changes we can make?
Aging is driven by many factors. At the cellular level aging is caused by damage to DNA and alterations to how it is expressed, along with the accumulation of molecular wastes. DNA also shortens every time a cell replicates; and the shortening end of DNA, known as a telomere, acts as a molecular clock. Inflammation is associated with oxidative stress that can damage DNA and proteins, as can toxins. The body must efficiently repair, recycle and clear damaged proteins and cells so that cellular waste products do not accumulate. Insulin plays a role in regulating blood sugar and causing the body to store fat, but has also been shown to act as a pro-aging molecule in animals like worms, independent of blood sugar. Animal models show that both insulin (which responds to consumption of sugar) and a pathway called mTOR (which responds to consumption of protein) are implicated in aging and can be targeted with drugs to increase lifespan.
These mechanisms largely explain why caloric restriction and fasting have been shown to reduce aging and increase longevity. Caloric restriction appears to slow the metabolism and the associated accumulation of toxic byproducts, reducing cellular damage. It increases insulin response. Fasting seems to suppress inflammation and promote a state where the immune system repairs and recycles damaged molecules, activating the sirtuin pathway for DNA and protein repair.
The benefits of exercise are widely known. Very large and convincing studies have shown no upper limit to the correlation between cardiovascular fitness and mortality. Individuals who can run on a treadmill longer demonstrate significantly lower all-cause mortality. Other studies have strongly correlated other factors, such as the ability to do more than 40 push-ups in males, with a significantly reduced risk of heart attack. In addition to maintaining the overall baseline functionality of the muscles, vasculature, and organs, exercise seems to be protective by stimulating the production of endogenous antioxidants such as superoxide dismutase and glutathione peroxidase which demonstrate antioxidant activity far in excess of that which can be achieved with dietary supplementation. For this reason antioxidant supplementation has lost popularity in life extension research in recent years.
Some specific foods and supplements have been shown to extend life and health span, mostly in animal models. While human trials are scant, food and supplements are available to everyone without a prescription. Foods and supplements that positively affect the sirtuin pathway have shown promise to improve the effects of aging in animal models. Resveratrol (found in grape seed extract and red wine) and some other related polyphenols activate this pathway. Sirtuins require a coenzyme, NAD+ (nicotinamide adenine dinucleotide), which increases the activity of sirtuins. Unfortunately, NAD+ decreases in abundance as people age. Increasing NAD+ concentrations in mice models through dietary supplementation has been shown to improve metrics of health and life span, like physical activity and life expectancy. NAD+ precursors include nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and niacin. Senolytics remove cells that have become senescent (or too old to function properly). These cells get in the body’s way and promote a toxic environment for the healthy cells. Fisetin is a flavonoid polyphenol that helps destroy senescent cells. It is found in many common fruits and vegetables. Eating fruits and vegetables that are high in nutrients and antioxidants and relatively low in calories (when compared to grains and processed foods) reduces the effects of aging and decreases risk for inflammatory processes and cancer. Polyphenols found in green tea have also been demonstrated to have absorbable antioxidant activity and to act as senolytics. Curcumin (found in turmeric) and Crocin (found in saffron) may delay cellular senescence and reduce inflammation via antioxidant mechanisms. Curcumin is thought to reduce the risk of some cancers’ formation and metastases. Crocin decreases the effects of UVB light on DNA, thus has potential to reduce skin damage (photoaging). Supplementation with collagen may reduce wrinkles and skin changes associated with aging. I recommend getting most of these foods through diet rather than dietary supplements.
A number of pharmaceutical drugs have shown promise in extending human health and life span. Metformin is a common first line type 2 diabetes treatment that has been shown to decrease mortality and morbidity from diabetes; and has shown protective effects in a variety of other conditions still being explored including cancers, kidney, cardiac, and Alzheimer disease; as well as in trials to treat aging and extend human lifespan. Metformin is a less toxic derivative of the molecule discovered in the medicinal plant Goat’s Rue. It has been around for decades, is available in generic form, and quite affordable. It acts by reducing blood sugar and inflammation as well as by improving lipid profile. It does not cause hypoglycemia because it acts in an insulin-independent manner. By reducing baseline blood glucose it decreases insulin resistance, lowering insulin secretion. When taken with meals it also reduces glucose absorption from the gut, preventing the absorption of calories. Acarbose, which also reduces glucose absorption from the gut, and pioglitazone, which increases insulin sensitivity, are other medications prescribed for diabetes that have been implicated as having life extending/anti aging potential. SGLT2 inhibitors like Farxiga, Jardiance, and Invokana also reduce blood sugars, the risk for cardiovascular events, and have been shown to be protective to the kidneys. These medications likely also act through some of the same mechanisms as caloric restriction.
One cannot help but reflect on the similarities between aging and poisoning. Smoking cigarettes and drinking alcohol, eating preserved meats, and using illicit drugs all promote aging because they are directly toxic both to tissues and at the molecular level. Alcohol alters lipid metabolism and promotes the deposit of fat in the liver. The polyphenols found in wine are linked to increased lifespan; but the damage that may be done to liver, heart and pancreas will likely reduce lifespan and healthspan in the setting of heavy drinking. These polyphenols can be found in other foods and supplements that are not also toxic. The medical community generally recommends a maximum of 7 alcoholic drinks in a week for women and 14 for men. In Britain (where alcohol usage is high) the NHS recommends taking at least one alcohol-free day weekly.
Getting enough sleep is critical. The body has a system called the glymphatic system that clears cellular wastes and recycles fluid in the brain, and this system works best when sleeping. Six to Eight hours of sleep a night is recommended for most adults. For some of us, our ability to sleep is diminished as we age. Daily exercise, time restricted feeding, and supplementation with melatonin (a neuroprotective antioxidant that aids in sleep) at night and NAD+ precursors in the morning can all improve circadian rhythm and reinforce good sleep habits.
Happiness and stress reduction are important to enjoying a long healthspan. To achieve this, I encourage nurturing social relationships. I also encourage goal oriented behavior; being more efficient, self disciplined, organized and deliberate in our actions. Seeking hobbies and educational pursuits. Risk for cardiovascular events and some cancers is increased with increased stress and misery. Being productive addresses anxiety and diminishes it directly. Boredom increases anxiety and reduces mental flexibility, potentially contributing to dementia. Exercise, in addition to the other benefits that it provides, decreases stress and produces natural endorphins that reduce pain and increases that overall satisfaction and sense of productivity that makes people feel good.
Brück Clift, MD 