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Living Longer in a Healthy Way

Researchers are trying to answer the question: can we live longer in a healthy way? Investments in life-extending drugs and clinical trials are on the rise regarding the subject. Remarkable innovations in medical care and the wide use of vaccines have been key to increasing life expectancy worldwide. The over-65-year-old global population has risen 468% between 1950 and 2020. In 2022, the average life expectancy of people in developed countries was 75 years for men and 82 for women, while globally it was 70 and 75 years, respectively, for men and women. Life expectancy in Nepal has risen to 71.45 years in 2022 from just 38.58 in 1960.

Many pioneering scientists are today focusing on the biology of aging, instead of spending time in finding cures for age-related diseases like Alzheimer’s, cataracts, and strokes. The U.S. National Institute on Aging’s Interventions Testing Program has discovered half a dozen drugs that extend the lifespan in a healthy way in mice, and at times, there has been excitement at discovering an anti-aging drug, such as the sirtuins about 15 years ago. Sirtuins are regarded as one of the most promising targets for anti-aging approaches, since they play a vital role in DNA damage response and repair, besides modulating oxidative stress and energy metabolism, thereby helping to sustain genome integrity.

Aging is marked by nine cellular processes that seem to change with age in effect, irrespective of whether one is in good or bad health. These processes provide the basis for research on aging at the cellular and subcellular level, and how to address them pharmaceutically. Since aging occurs at the cellular level, it is a major risk factor for almost all chronic diseases, cancer, and neurodegenerative diseases, with 95% of those 65 and older having at least one chronic disease, and about 75% having two or more. Even during the recent pandemic, the risk of dying from COVID-19 was seen to increase sharply with age. Compared to those in their 20s, the chances of dying was found to be 140 times higher for those over 75, and 330 times higher for those over 85 years.

Some anti-aging drugs could potentially reduce the risk of multiple age-related illnesses simultaneously, and the goal of these pioneering researchers is to develop a multimorbidity prevention drug that will target different cellular mechanisms related to aging. They have also found that centenarians live longer not because they’re less susceptible to any one specific disease, but because they’re less susceptible to all of them. They seem to live quite well even though they do not really follow an especially healthier lifestyle compared to other folks, such as exercising a lot or eating a Mediterranean diet, or never having smoked a cigarette in their lives.

The fact that the global population of those 65 and older rose 468% between 1950 and 2020, and is expected to rise 113% more by 2050, assures a huge market for pharma companies to develop drugs that will slow the disease process or prevent disease, thus extending lifespans, along with improving the quality of life. No wonder then that they are investing in the billions for studies and clinical trials on anti-aging candidate molecules. Some companies are working on vaccines that target drug-resistant pathogens, the aim being to come up with a vaccine plan for older adults targeting different infectious diseases.

It is interesting that metformin, a cheap and readily available anti-diabetic, is one of the first drugs being trialed to prevent age-related diseases, focusing on people who are 65 plus. While regulators have approved drugs to address risk factors like hypertension, high cholesterol, blood sugar imbalances, and even lifestyle factors like smoking and obesity, to approve drugs specifically to treat aging as a risk factor, aging biomarkers have to be developed. The whole idea of extending our lives healthily makes this field of research full of exciting potential.

1. Bio World, July 17, 2022, https://bit.ly/3hddhqp
2. Statista, Oct 20, 2022, https://bit.ly/2RKwFIP


Does Metformin Slow Down Aging?

Metformin is a synthetic biguanide that was first introduced to treat type 2 diabetes mellitus (T2DM) in France in 1958, and is still the first-line treatment for T2DM in many cases. It is an inexpensive and safe drug, with side effects primarily being abdominal pain, bloating, diarrhea, nausea, and vomiting. A 2021 critical review states that its wider use as a prophylactic to offset the effects of aging and enhance health span and lifespan could be justified, based on extensive literature supporting the benefits of metformin in the settings of diabetes, obesity, cardiovascular disease and perhaps cancer and dementia. While the review noted that metformin was found to increase life span and delay the onset of age-related health decline in animal studies, other clinical trials indicate that metformin may reduce chronic inflammation, which increases the risk of age-related conditions like heart disease and neurodegenerative conditions. Metformin may also slow the aging process by its direct protective effects on vascular function, improving blood flow and providing protection against age-related cognitive decline. Ongoing research suggests that metformin may cause a hormesis effect (a process in which minor stress can activate intra-cellular processes that help repair damage and protect cells) by activating the AMP-activated protein kinase enzyme, which helps to break down excess lipids and sugars in the body.

Ref: Front. Endocrinol., August 5, 2021, https://www.rontiersin.org/articles/10.3389/fendo.2021.718942/full

The Hallmarks of Aging

1. Genomic instability
A common denominator of aging is the accumulation of genetic damage throughout life.

2. Telomere attrition
Some chromosomal regions, such as telomeres, are particularly susceptible to age-related deterioration.

3. Epigenetic alterations
Epigenetic alterations involving alterations in DNA methylation patterns, post-translational modification of histones, and chromatin remodeling, affects all cells and tissues throughout life.

4. Loss of proteostasis
Aging and some aging-related diseases are linked to impaired protein homeostasis or proteostasis.

5. Deregulated nutrient-sensing
Available evidence indicates that anabolic signaling accelerates aging, while decreased nutrient signaling extends longevity.

6. Mitochondrial dysfunction
The mitochondrial free radical theory proposes that progressive mitochondrial dysfunction results in increased production of reactive oxygen species, which causes further mitochondrial deterioration and global cellular damage.

7. Cellular senescence
Pervasive damage and the deficient clearance and replenishment of senescent cells results in their accumulation, which has deleterious effects on tissue homeostasis that contribute to aging.

8.  Stem cell exhaustion
Decline in the regenerative potential of tissues is an obvious characteristic of aging.

9. Altered intercellular communication
Aging also involves changes at the level of intercellular communication (endocrine, neuroendocrine, or neuronal).

Ref: National Center for Biotechnology Information, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/


The TAME Trial

The Targeting Aging with Metformin (TAME) Trial is a series of six-year clinical trials by the American Federation for Aging Research (AFAR) that will be held at 14 leading research institutions across the United States with over 3,000 participants between the ages of 65-79 years. Led by AFAR Scientific Director Nir Barzilai, MD, the trials will examine whether those taking metformin have delayed development or progression of age-related chronic diseases like heart disease, cancer, and dementia.

Metformin has been used successfully to treat type 2 diabetes mellitus for more than 60 years. Earlier animal models and in vitro studies studies have shown that metformin can delay aging by influencing metabolic and cellular processes, such as inflammation, oxidative damage, diminished autophagy, cell senescence, and apoptosis, which are.associated with the development of age-related conditions. Although other promising drugs are also under trial targeting aging, TAME will focus on metformin because of its safety and low cost.

TAME aims to provide proof-of-concept that aging can be treated, just like other diseases, and hopes that the FDA will approve aging as an indication (an “indication” for a drug refers to the use of that drug for treating a particular condition). If so, the TAME Trial will succeed in having age per se targeted for treatment, instead of treating age-related medical conditions separately. If aging is made an indication for treatment, a new era of treatments will be available by creating new opportunities for biotech innovation and investment. The trial will also include a concurrent study, TAME BIO, the aim of which is to enhance understanding of the biomarkers of aging.

Ref: AFAR, https://www.afar.org/tame-trial

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