Tag Archives: senescent cells

Future of Anti-aging Medication: Senotherapy

Individual controls aging, ,

Introduction

Because all of our life phases (birth to adulthood) are driven by genetic programs, one naturally assumes genetic programs dictate age changes.  Sadly, they do not (see Insight 1).  In fact our genes contribute at most, 25% to aging.  Thus, 75% of aging is due to one’s lifestyle choices.

Unfortunately, study results show that only a small percentage of elderly actually practice validated and effective activities to minimize aging.  Therefore, for the majority of elderly, this blog brings deliverance in the knowledge of the rapidly developing pharmacological field of senotherapy, with the purpose to reduce disease risk by retarding aging.  It is hoped that senotherapy becomes a supplement to anti-aging lifestyle choices practiced by the individual.

This blog will discuss senotherapy and its merits.  However, since safe and effective senotherapy is not available today but clearly in expected in the near future, it is worthwhile to review known beneficial and anti-aging lifestyle choices.

Proven Activities to Retard Aging

Until senotherapy is common practice, there are many effective ways to retard aging and hence, reduce the risk for disease.  Some of these activities are: 

Pro-Active

1.  COMMITMENT TO A COMPLETE EXERCISE PROGRAM that includes aerobics and stretch (Insight 4: Anti-aging benefits of aerobic and stretch exercises), resistance exercises (Insight 2), balance exercises (Insight 5) .  Numerous benefits include enhanced blood flow to all tissues, stable heart function, stronger muscles, greater flexibility and balance. These all translate into greater independence, reduced risk of falls and decreased disease risk. Other benefits include improved insulin sensitivity especially benefiting from a program of resistance exercise (Insight 18 Vicious Cycle – Aging and Declining Blood Sugar Control).

2.  ADHERENCE TO THE MEDITERRANEAN DIET, a plant-based diet  reduces risks for many diseases including type 2 diabetes, cardiovascular disease, cancers, Alzheimer’s and Parkinson’s diseases (Insight 10). 

3,  PRACTICE OF POSITIVE NEUROPLASTICITY that consist of a) continual engagement in career activities by not retiring, part time retirement, volunteer work or a new career, b) learning new skills e.g. foreign language or musical instrument, c) maintaining social contacts and d) physical exercise program (Insight 6 ).  These activities promote optimal brain function.

4.  AWARENESS OF SPECIFIC MAINTENANCE/PRESERVATION ACTIVITIES OF SENSORY ORGANS can preserve normal sight, hearing, smell and tactile/proprioceptive senses.  This awareness includes use of reading glasses to correct age-related loss of near vision; avoidance of exposure to chronic loud noises e.g. rock concerts, yard tools, to prevent hearing loss (Insight 16 How to Prevent Hearing Loss ), avoidance of exposure to harsh chemicals e.g. Clorox to prevent decline in smell and routine balance exercises to prime sensory neurons (proprioceptors) in joints, ligaments, muscles (Insight 5 – Optimizing Balance).  Accidents, falls, fuzzy thinking results from diminished sensory function.  Physiologically normal sensory function is essential for independent living.    

Avoidance

1.  CHOOSE ACTIVITIES THAT AVOID THE FOLLOWING:   UVA radiation is a known cause of aging skin and skin cancer.  The risk of both are lessened dramatically with routine use of sunscreens, termed broad spectrum.  Compounds classified as broad spectrum sunscreens specifically block UVA  rays from penetrating deep into the skin (Insight 12 -Ways to forestall aging of the skin). 

2. Avoidance of tobacco smoking is absolutely necessary to prevent accelerated aging and enhanced risk of disease including cardiovascular and cancer diseases.  Each inhalation brings in over 1000 toxins that damage precious molecules e.g. DNA, proteins, and lipids.  There are several ways to quit smoking.  Success can result from use of nicotine replacement therapies such as transdermal nicotine patch, nicotine gum, nicotine lozenge and/or pharmaceuticals such as the anti-depressant, bupropion (Zyban) or partial nicotine agonist, varenicline (Chantix) plus physician support with advice and behavioral therapy.

Anti-aging Medication: Senotherapy

Senotherapy is the pharmacological approach to eliminate or modify aged or senescent cells.  This approach will undoubtedly serve those who choose to ignore the clinically proven activities discussed above to retard aging and reduce the risk for disease.  The validated activities delineated above are critically important because they reduce the stress-related factors that cause a cell to age.

Background on Senotherapy

It has been known for some time now that as one ages, the cells in each tissue begin to change.  They increase in size, cease normal function and become bad actors, producing a myriad number of unwanted substances e.g. pro-inflammatory and other destructive agents that harm near-by healthy cells.  Sadly, senescent cells skirt around the biological mechanisms to identify and eliminate them.  Hence, their presence clearly promotes aging of tissues and sets the stage for the first steps to disease.

In consideration of the serious consequences of persistent senescent cells, research interest in senotherapy has blossomed significantly.  Approximately 12 compounds have been evaluated in aged mice or mouse models of disease.  The results of these studies have in many cases been dramatic with reduction in the number of senescent cells and their debilitating functions.  For example, reports show benefits on improved function in kidneys, skeletal muscles, liver and lungs.  Also reported were reduced inflammation in the brain, and increased skeletal muscle regeneration.  

Pilot Studies in Man

Several small pilot studies in man have used senotherapy in conditions of pulmonary fibrosis, macular degeneration, and cardiovascular disease.  Although the results are promising, caution is needed since these studies were of short duration (days/weeks), included few participants (7-13) and used a single dose.  Future studies will surely address these issues and others such as long term adverse effects.

Summary of discussion on anti-aging strategies. What the individual can do and what might be in the future as an aid.
Anti-aging Strategies

Conclusions

In this rush to pharmacologically retard aging, we should not ignore the wealth of data from clinical trials that already exists to minimize cellular aging as continually discussed in prior blogs.  Senotherapy seeks to develop selective drugs to eliminate or minimize the effects of aged cells.  Scientific interest is high because aging is the main risk factor for disease, so to eliminate age changes will significantly decrease disease incidence. 

Select reference (Pubmed)

Bilder, G. Human Biological Aging: from macromolecules to organ-systems.  John Wiley & Sons Publishers, Hoboken, New Jersey, 2016.

Iftikhar U et al., How to Effectively Help Patients Stop Smoking: A Primer for Cardiologists. Canadian Journal of Cardiology 38: 1442-1445, 2022.

Justice JN et al., Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine 40:554-563, 2019.

L’Hote V. et al., From the divergence of senescent cell fates to mechanisms and selectivity of senolytic . Open Biol. 12: 220171, 2022.

Raffaele M., Vinciguera M. The costs and benefits of senotherapeutics for human health.  Lancet Healthy Longev 3: e67–77, 2022.

West, R.  Tobacco smoking: Health impact, prevalence, correlates and nterventions. Psychology & Health,  32:  1018-1036, 2017.

Insight 12 -Ways to forestall aging of the skin

Individual controls aging, Skin aging, , , , ,

Introduction

Despite the growing number of individuals joining the ranks of senior citizens, our culture remains focused on its youth and hence, there exists the pressure to stay young as long as possible.  The desire to preserve a youthful appearance is encouraged by the development of an abundance of cosmetics, creams, lotions, injections, chemical processes and surgical procedures to prevent, minimize or remove wrinkles, sags and fine lines.  These treatments are effective but undoubtedly expensive.  At the top of the list is the surgical face lift that lasts years, then injections of fillers of collagen or matrix-derived compounds needed every 8 months or so, and Botox injections that relax skeletal muscles and last several months.

However, understanding the science of aging skin allows one to sidestep these costly treatments and to minimize wrinkles, sags and fine lines with the least expense possible.  The two least expensive effective products to use are:  broad spectrum sunscreens and the retinoids.  Since 70% of age changes are controlled by the individual (see Insight 1), use of these products allows individual control.

Additionally, in reducing wrinkles and sags, many more important benefits occur. These benefits are:

(1)  reduced risk of skin cancers

(2)  improved skin blood flow assuring health of the skin and

(3)  retention of resident immune cells as first line of defense against infections. 

This blog will elucidate the essential knowledge on aging skin so as to achieve these essential benefits.

Verified age changes in the skin

Extrinsic/Intrinsic Aging

There are two types of aging processes that affect the skin:  extrinsic and intrinsic.  The former results from chronic exposure to externally generated irritants such as ultraviolet radiation (UVR), extreme temperatures and pollutants.  Extrinsic aging, commonly called photoaging, harms the exposed (unclothed) skin of the face, neck, arms, and legs.  Extrinsic factors rapidly accelerate the aging process and establish irreversible changes.

In contrast, intrinsic aging, also called normal aging, occurs very slowly as a result of internal changes such as nutrient availability, inflammatory damage and oxidative events.  Intrinsic aging occurs in areas that are usually covered by clothing or are hidden (such as the chest and back, buttock, underarms and behind the ears).  External factors have little effect on protected areas.  

There are three distinct layers to the skin : epidermis (top), dermis (middle) and hypodermis (bottom).  Because each layer contains different cells and relevant support material, each layer ages differently.  Since the focus of this blog is to discuss how to minimize wrinkles, sags and fine lines, only extrinsic aging which is the main cause of wrinkles, sags and fine lines,  will be detailed.

Wrinkles, sags, fine lines

Facial wrinkles develop mainly through external damage from solar ultraviolet radiation (UVR).  UVR consists of 3 different wave components:  UVA, UVB and UVC.  UVC is of no consequence as it does not enter the atmosphere.  UVA and UVB penetrate the atmosphere and injure human skin.

Epidermis of the skin

UVB penetrates the epidermis, the top layer of the skin but no more.  Too much UVB causes a sunburn.  Chronic UVB exposure irritates resident cells of the epidermis, called epithelial cells, and eventually induces a unnatural thickening of this outer layer. 

Dermis of the skin

Unlike UVB, UVA is insidious since it does not produce overt effects such as sunburn.  UVA penetrates down to the second layer of the skin, the dermis and damages the fibroblasts, the cells tasked with housekeeping duties of the dermis.  Fibroblasts traumatized by UVA progress to a terminal stage loosely termed senescent cells or scientifically termed, the senescent-associated secretory phenotype (SASP). 

SASP cells become tragic residents of the dermis because they are dramatically and permanently altered to cause chronic damage to the dermis.  These converted cells are notoriously harmful because:

(1)  the SASP is unable to divide and hence cannot renew itself, an effective way to eliminate oxidized compounds,

(2)  SASP aberrant function replaces normal fibroblast function. Consequently, the SASP produces an abundance of unwanted inflammatory mediators and harmful enzymes .  These substances destroy the support platform of the dermis.   

(3)  despite the harmful effects of the SASP, this cell type persists.  It is immune to cellular mechanisms to destroy it.

Consequently, these changes allow for gravity to overcome the  deteriorating weakened structure of the dermis to produce wrinkles and sags.  UVA-induction of the SASP is central to wrinkles and sags. 

Hypodermis of the skin

The hypodermis is the fatty layer under the dermis.  It, too, is affected by external damage from UVA.  Combined with normal aging, the hypodermis decreases in thickness.  Additionally, the matrix supporting the fat cells deteriorates and fat cells lose functionality, size and adherence to the dermal layer.  Thus another layer of support is modified in favor of wrinkles and sags.

Therefore, UVR-induced changes in the epidermis, dermis and hypodermis reduce the mechanical strength of the facial skin and other exposed skin and allow the forces of gravity to exert their effects, creating wrinkles and sags.  This is mainly brought about with chronic exposure to UVA.

Prevention of wrinkles and sags

Broad Spectrum Sunscreens

Since UVR is the major instigator of facial wrinkles and sags, blocking UVR with a sunscreen is a reasonable solution.  However, it was not until 2012 that the FDA approved the addition of UVA-blocking compounds in sunscreens.  Prior to this date, sunscreen only contained UVB-blocking substances to prevent sunburns. 

UVB blockers were termed sun protection factors (SPFs) and sunscreens were labeled according to the blocking strength of the UVB compound.  SPF ranges in strength from 15 to 75 or more.  With the realization that UVA, not UVB, causes skin cancers and facial aging, approval was granted to add UVA-blocking compounds to sunscreens.  Hurrah!!  Sunscreens with these compounds and UVB-blockers are now called broad spectrum sunscreens with SPF.  If used correctly (according to the directions), broad spectrum sunscreens will block both UVA and UVB radiation.  Chronic use of the broad spectrum sunscreens from a young age onward will significantly reduce wrinkles and sags. 

Two issues of importance: 

Firstly,  the compounds blocking UVA are of two types, ones that are absorbed and ones that are not.  Avobenzene belongs to the former; zinc oxide belongs to the latter.  So far both are considered safe but controversy has arisen regarding the safety of the absorbable anti-UVA compounds. 

Secondly, the chronic use of sunscreens limits the production of vitamin D in the skin.  If sunscreens are used constantly, this source of  vitamin D is inhibited and additional sources of vitamin D, e.g.  foods fortified with vitamin D or from supplements, are required.

Retinoids

Since protection against UVA was not available until 2012, most elderly today received generous amounts of UVA that caused facial wrinkles and sags.  To ameliorate this, the family of retinoids (retinol, retinaldehyde, retinoic acid also known as tretinoin), are beneficial.  Retinoids are essentially different forms of vitamin A.  When applied to the skin, retinoids reduce the photoaging effects of UVA.  In a number of small clinical trials, topical application of these compounds reversed or minimized age-associated facial lines, and wrinkles. 

It is known that retinoids activate epidermal and dermal cells with the result of enhancement of cell renewal, increased blood flow and maintenance of the dermal structure. Hence, retinoids reverse the damaging effects of UVA. 

The single major adverse effect with use of  retinoids is skin irritation or rash.  The mechanism for this is unknown and under investigation.   

Conclusions

Chronic external damage (mainly UVA) to a large portion of the skin causes wrinkles, sags and fine lines.  These are changes with serious psychological effects.  Importantly, underlying this is reduced physiological function of the skin that gives rise to skin cancers, poor wound healing and decreased defense against bacterial infections.

Use of broad spectrum sunscreens and retinoids protects the skin against extrinsic age changes. This assures many excellent benefits ranging from reduction in wrinkles and sags to optimal wound healing and decreased risk of skin cancers.